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Jiao Y, Ho I, Li T, Na R, Wong C, Wang J, Siu SWK, Wei Y, Chen Y, Chan EW, Li X. Real-world effectiveness of novel hormonal agents and docetaxel in patients with prostate cancer: A head-to-head comparison. iScience 2025; 28:112249. [PMID: 40241770 PMCID: PMC12001135 DOI: 10.1016/j.isci.2025.112249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 11/01/2024] [Accepted: 03/17/2025] [Indexed: 04/18/2025] Open
Abstract
Next-generation hormonal-targeted therapies for advanced prostate cancer are widely used. We aimed to evaluate the effectiveness and health resource utilization (HRU) of novel hormonal agents (NHAs) compared to chemotherapy in a real-world context. After propensity score matching, survival analysis revealed no significant difference in overall survival between the individuals treated with NHAs and those treated with docetaxel (hazard ratio [HR]: 1.00, 95% confidence interval [CI]: 0.89-1.11) in the cohort of 1,056 patients. Similar results were observed for prostate-specific antigen (PSA) progression-free survival (HR: 1.02, 95% CI: 0.91-1.14) and PSA response rate (72% [95% CI: 68-76%] for NHAs vs. 76% [95% CI: 72-80%] for docetaxel, p > 0.05). Additionally, patients treated with NHAs had a significantly lower annual HRU during follow up. These findings indicate comparable effectiveness between NHAs and chemotherapy, with a more favorable HRU profile for NHA-treated patients, suggesting potential cost-effectiveness of NHAs.
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Affiliation(s)
- Yuanshi Jiao
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Isaac Ho
- Department of Clinical Oncology, Queen Mary Hospital, Hong Kong SAR, China
| | - Tunghiu Li
- Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Rong Na
- Department of Surgery, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Chunka Wong
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Jiaqi Wang
- Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | | | - Yan Wei
- School of Public Health, Fudan University, Shanghai 200433, China
- National Health Commission Key Laboratory of Health Technology Assessment, Fudan University, Shanghai 200433, China
| | - Yingyao Chen
- School of Public Health, Fudan University, Shanghai 200433, China
- National Health Commission Key Laboratory of Health Technology Assessment, Fudan University, Shanghai 200433, China
| | - Esther W. Chan
- Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- Laboratory of Data Discovery for Health (D4H), Hong Kong SAR, China
| | - Xue Li
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- Laboratory of Data Discovery for Health (D4H), Hong Kong SAR, China
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Yu EY, Berry WR, Gurney H, Retz M, Conter HJ, Laguerre B, Fong PCC, Ferrario C, Todenhöfer T, Gravis G, Piulats JM, Emmenegger U, Shore ND, Romano E, Mourey L, Li XT, Poehlein CH, Schloss C, Appleman LJ, de Bono JS. Pembrolizumab and Enzalutamide in Patients with Abiraterone Acetate-Pretreated Metastatic Castration-Resistant Prostate Cancer: Cohort C of the Phase 1b/2 KEYNOTE-365 Study. Eur Urol Oncol 2024; 7:509-518. [PMID: 37940446 DOI: 10.1016/j.euo.2023.10.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 09/29/2023] [Accepted: 10/10/2023] [Indexed: 11/10/2023]
Abstract
BACKGROUND Limited responses have been observed in patients treated with enzalutamide after disease progression on abiraterone for metastatic castration-resistant prostate cancer (mCRPC), but androgen receptor signaling impacts T-cell function. OBJECTIVE To evaluate the efficacy and safety of pembrolizumab plus enzalutamide in mCRPC. DESIGN, SETTING, AND PARTICIPANTS Patients in cohort C of the phase 1b/2 KEYNOTE-365 study, who received ≥4 wk of treatment with abiraterone acetate in the prechemotherapy mCRPC state and experienced treatment failure or became drug-intolerant, were included. INTERVENTION Pembrolizumab 200 mg intravenously every 3 wk plus enzalutamide 160 mg orally once daily. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary endpoints were safety, the confirmed prostate-specific antigen (PSA) response rate, and the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors version 1.1 on blinded independent central review (BICR). Secondary endpoints included radiographic progression-free survival (rPFS) on BICR and overall survival (OS). RESULTS AND LIMITATIONS A total of 102 patients received pembrolizumab plus enzalutamide. Median follow-up was 51 mo (interquartile range 37-56). The confirmed PSA response rate was 24% (95% confidence interval [CI] 16-33%). The confirmed ORR was 11% (95% CI 2.9-25%; 4/38 patients; two complete responses). Median rPFS was 6.0 mo (95% CI 4.1-6.3). Median OS was 20 mo (95% CI 17-24). Treatment-related adverse events (TRAEs) occurred in 94 patients (92%); grade 3-5 TRAEs occurred in 44 patients (43%). The incidence of treatment-related rash was higher with combination therapy than expected from the safety profile of each drug. One patient (1.0%) died of a TRAE (cause unknown). Study limitations include the single-arm design. CONCLUSIONS Pembrolizumab plus enzalutamide had limited antitumor activity in patients who received prior abiraterone treatment without previous chemotherapy for mCRPC, with a safety profile consistent with the individual profiles of each agent. PATIENT SUMMARY Pembrolizumab plus enzalutamide showed limited antitumor activity and manageable safety in patients with metastatic castration-resistant prostate cancer. The KEYNOTE-365 trial is registered on ClinicalTrials.gov as NCT02861573.
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Affiliation(s)
- Evan Y Yu
- Division of Hematology and Oncology, Fred Hutchinson Cancer Center and University of Washington, Seattle, WA, USA.
| | | | - Howard Gurney
- Department of Clinical Medicine, Macquarie University, Sydney, Australia
| | - Margitta Retz
- University Hospital Rechts der Isar, Technical University of Munich, Munich, Germany
| | | | | | | | | | | | | | | | - Urban Emmenegger
- Division of Medical Oncology, Odette Cancer Centre, Toronto, Canada
| | - Neal D Shore
- Carolina Urologic Research Center, Myrtle Beach, SC, USA
| | - Emanuela Romano
- Department of Oncology, Center for Cancer Immunotherapy, Institut Curie, Paris, France
| | - Loic Mourey
- Department of Medical Oncology, Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France
| | | | | | | | | | - Johann S de Bono
- The Institute of Cancer Research, The Royal Marsden Hospital, London, UK
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Xiong X, Zhang S, Zheng W, Liao X, Yang J, Xu H, Hu S, Wei Q, Yang L. Second-line treatment options in metastatic castration-resistant prostate cancer after progression on first-line androgen-receptor targeting therapies: A systematic review and Bayesian network analysis. Crit Rev Oncol Hematol 2024; 196:104286. [PMID: 38316286 DOI: 10.1016/j.critrevonc.2024.104286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Revised: 01/22/2024] [Accepted: 01/31/2024] [Indexed: 02/07/2024] Open
Abstract
OBJECTIVE To summarize and indirectly compare the efficacy and safety of different second-line systematic therapies after first-line androgen-receptor targeting therapies (ARTs) for biomarker-unselected metastatic castration-resistant prostate cancer (mCRPC) patients. METHODS Studies published in English up to May 2023 were identified in PubMed, Web of Science and ASCO-GU 2023. Studies accessing the efficacy and safety of second-line systematic therapies after first-line ARTs for biomarker-unselected mCRPC patients were eligible for current systematic review and network meta-analysis (NMA). RESULTS Thirty-two studies with 5388 patients and 10 unique treatment modalities met our inclusion criteria. Current evidence suggested that docetaxel (DOC) combined with the same ART as first-line (ART1) (ART1 + DOC) were associated with significantly improved PSA response, PSA progression-free survival (PFS) and clinical or radiographic PFS (rPFS) compared with other reported second-line systematic therapies, including DOC. An increase in toxicity was observed with ART1 + DOC. Our NMA indicated that DOC monotherapy was only inferior to ART1 + DOC in improvement disease outcomes. The incidence of toxicity between patients received second-line DOC and an alternative ART (ART2) was similar. CONCLUSION The available evidence reviewed in our work suggested a clinical benefit of DOC nomotherapy and DOC plus ART1 as the second-line systematic therapy for biomarker-unselected mCRPC patients progressed on a first-line ART. More studies and RCTs are needed to evaluate the optimal second-line treatments for mCRPC patients with one prior first-line ART.
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Affiliation(s)
- Xingyu Xiong
- Department of Urology, West China Hospital of Sichuan University, 610000 Chengdu, Sichuan Province, China; Institute of Urology, West China Hospital of Sichuan University, 610000 Chengdu, Sichuan Province, China
| | - Shiyu Zhang
- Department of Urology, West China Hospital of Sichuan University, 610000 Chengdu, Sichuan Province, China; Institute of Urology, West China Hospital of Sichuan University, 610000 Chengdu, Sichuan Province, China
| | - Weitao Zheng
- Department of Urology, West China Hospital of Sichuan University, 610000 Chengdu, Sichuan Province, China; Institute of Urology, West China Hospital of Sichuan University, 610000 Chengdu, Sichuan Province, China
| | - Xinyang Liao
- Department of Urology, West China Hospital of Sichuan University, 610000 Chengdu, Sichuan Province, China; National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, 610000 Chengdu, Sichuan Province, China
| | - Jie Yang
- Department of Urology, West China Hospital of Sichuan University, 610000 Chengdu, Sichuan Province, China; Institute of Urology, West China Hospital of Sichuan University, 610000 Chengdu, Sichuan Province, China
| | - Hang Xu
- Department of Urology, West China Hospital of Sichuan University, 610000 Chengdu, Sichuan Province, China; National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, 610000 Chengdu, Sichuan Province, China
| | - Siping Hu
- National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, 610000 Chengdu, Sichuan Province, China
| | - Qiang Wei
- Department of Urology, West China Hospital of Sichuan University, 610000 Chengdu, Sichuan Province, China; National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, 610000 Chengdu, Sichuan Province, China.
| | - Lu Yang
- Department of Urology, West China Hospital of Sichuan University, 610000 Chengdu, Sichuan Province, China; Institute of Urology, West China Hospital of Sichuan University, 610000 Chengdu, Sichuan Province, China.
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Lukashchuk N, Barnicle A, Adelman CA, Armenia J, Kang J, Barrett JC, Harrington EA. Impact of DNA damage repair alterations on prostate cancer progression and metastasis. Front Oncol 2023; 13:1162644. [PMID: 37434977 PMCID: PMC10331135 DOI: 10.3389/fonc.2023.1162644] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 06/01/2023] [Indexed: 07/13/2023] Open
Abstract
Prostate cancer is among the most common diseases worldwide. Despite recent progress with treatments, patients with advanced prostate cancer have poor outcomes and there is a high unmet need in this population. Understanding molecular determinants underlying prostate cancer and the aggressive phenotype of disease can help with design of better clinical trials and improve treatments for these patients. One of the pathways often altered in advanced prostate cancer is DNA damage response (DDR), including alterations in BRCA1/2 and other homologous recombination repair (HRR) genes. Alterations in the DDR pathway are particularly prevalent in metastatic prostate cancer. In this review, we summarise the prevalence of DDR alterations in primary and advanced prostate cancer and discuss the impact of alterations in the DDR pathway on aggressive disease phenotype, prognosis and the association of germline pathogenic alterations in DDR genes with risk of developing prostate cancer.
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Affiliation(s)
- Natalia Lukashchuk
- Translational Medicine, Oncology Research and Development (R&D), AstraZeneca, Cambridge, United Kingdom
| | - Alan Barnicle
- Translational Medicine, Oncology Research and Development (R&D), AstraZeneca, Cambridge, United Kingdom
| | - Carrie A. Adelman
- Translational Medicine, Oncology Research and Development (R&D), AstraZeneca, Cambridge, United Kingdom
| | - Joshua Armenia
- Oncology Data Science, Oncology Research and Development (R&D), AstraZeneca, Cambridge, United Kingdom
| | - Jinyu Kang
- Global Medicines Development, Oncology Research and Development (R&D), AstraZeneca, Gaithersburg, MD, United States
| | - J. Carl Barrett
- Translational Medicine, Oncology Research and Development (R&D), AstraZeneca, Waltham, MA, United States
| | - Elizabeth A. Harrington
- Translational Medicine, Oncology Research and Development (R&D), AstraZeneca, Cambridge, United Kingdom
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Moldaver DM, Hassan S, Seung SJ, Edwin J, Clouthier DL, Vera-Badillo FE. A real-world retrospective analysis of the management of metastatic castrate-resistant prostate cancer in Ontario, Canada from 2010 - 2018. Urol Oncol 2023; 41:146.e13-146.e22. [PMID: 36641303 DOI: 10.1016/j.urolonc.2022.11.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 10/28/2022] [Accepted: 11/27/2022] [Indexed: 01/13/2023]
Abstract
PURPOSE We sought to quantify mCRPC patient treatment patterns and survival across multiple lines of therapy after prior androgen-receptor-axis-targeted therapy (ARAT) failure. METHODS Individuals diagnosed with prostate cancer between 2010 and 2018 were identified in the Ontario Cancer Registry (OCR). An algorithm was created to identify patients with mCRPC that was aligned to Prostate Cancer Clinical Trials Working Group 3 criteria (PCWG3) and validated with Canadian clinical experts. In the mCRPC setting, treatment patterns were assessed by line of therapy, and survival was calculated from treatment initiation until death or lost to follow-up. RESULTS 64,484 men were diagnosed withprostate cancer in Ontario between 2010 and 2018with 5,588 men assessed to have mCRPC and 2,970 (53%) of those received first-line systemic treatment. Across the first-, second- and third-line of therapy, ARATs (abiraterone and enzalutamide) were the most used therapies. Survival for mCRPC patients treated with ARATs in first-, second- and third-line were 13.0 (95% CI, 11.6 - 14.5), 11.5 (95% CI, 10.1 - 13.4) and 8.9 (95% CI, 7.4 - 10.2) months, respectively. Survival for mCRPC patients treated with taxanes in first, second- and third-line were 16.7 (95% CI, 14.8 - 18.0), 11.3 (95% CI, 10.1 - 12.5) and 7.8 (95% CI, 6.5 - 10.6) months, respectively. No statistical difference in overall survival was found between taxanes and ARATs. CONCLUSION In this analysis of a large retrospective cohort of Canadian men with mCRPC, we found that survival in patients treated with ARATs and taxanes was fairly similar across all lines of therapy. Importantly, this trend was maintained in ARAT-exposed patients, where sequential ARAT and taxanes offered similar survival. These data may help inform optimal sequencing of therapies in mCRPC.
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Affiliation(s)
| | - Shazia Hassan
- HOPE Research Centre, Sunnybrook Research Institute, Toronto, ON
| | - Soo Jin Seung
- HOPE Research Centre, Sunnybrook Research Institute, Toronto, ON
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Broyelle A, Delanoy N, Bimbai AM, Le Deley MC, Penel N, Villers A, Lebellec L, Oudard S. Taxanes Versus Androgen Receptor Therapy as Second-Line Treatment for Castrate-Resistant Metastatic Prostate Cancer After First-Line Androgen Receptor Therapy. Clin Genitourin Cancer 2023; 21:349-356.e2. [PMID: 36935298 DOI: 10.1016/j.clgc.2023.02.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 02/09/2023] [Accepted: 02/13/2023] [Indexed: 02/18/2023]
Abstract
BACKGROUND The optimal therapeutic sequence for metastatic castrate-resistance prostate cancer (mCRPC) is still debated. This study aimed to compare activity of taxanes (TAX) versus that of androgen-receptor therapy (ART) in men with mCRPC treated with first-line ART. PATIENTS AND METHODS This retrospective study included all consecutive chemo-naive mCRPC patients who have received first-line ART treatment. Progression-free survival (PFS) and overall survival (OS) were compared between patients treated with second-line ART or TAX. RESULTS Overall, 175 patients treated with first-line enzalutamide (ENZA, n = 75) or abiraterone (ABI, n = 100) were evaluated. Among them, 69 (39%) and 30 (17%) patients received second-line TAX and ART, respectively, while 76 (43%) patients did not receive further treatment. From the start of first-line therapy, the median PFS and OS were 13 months (95% CI: 11-15) and 34 months (95% CI: 29-39), respectively, without any significant difference between ENZA and ABI. From the start of second-line therapy, the median PFS and OS were 6 months (95% CI: 5-7) and 18 months (95% CI: 14-21), respectively. Compared with ART, docetaxel was associated with significantly higher prostate-specific antigen (PSA, ≥ 50%) (29% vs. 0%, P < .001) and radiological responses (21% vs. 0%, P < .001). PFS was longer in TAX than in ART (6.7 months vs. 4 months, HR: 0.63, 95% CI: 0.41-0.96, P = .034), but there was no significant difference in OS (19 months vs. 12 months, P = .1). After propensity score adjustment, PFS (P = .2) and OS (P = .1) were similar between second-line TAX and ART. CONCLUSION In the second-line setting, TAX provides higher PSA and radiological responses than does ART for mCRPC patients who received first-line ART, but the PFS and OS are similar. This study provides new elements to help deciding the best treatment sequence.
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Affiliation(s)
- Antonin Broyelle
- Medical Oncology Department, Centre Oscar Lambret, Lille, France.
| | - Nicolas Delanoy
- Medical Oncology Department, Hopital Européen Georges Pompidou, Paris, France; Paris Cité University, Medical School, Paris, France
| | | | | | - Nicolas Penel
- Medical Oncology Department, Centre Oscar Lambret, Lille, France; Lille University, Medical School, Lille, France
| | - Arnauld Villers
- Urology Department, Hopital Claude Huriez, Lille University Hospital, Lille, France; Lille University, Medical School, Lille, France
| | - Loïc Lebellec
- Medical Oncology Department, Centre Oscar Lambret, Lille, France
| | - Stéphane Oudard
- Medical Oncology Department, Hopital Européen Georges Pompidou, Paris, France; Paris Cité University, Medical School, Paris, France
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Teply BA, Antonarakis ES. The evolving landscape of PARP inhibitors in castration-resistant prostate cancer: a spotlight on treatment combinations. Expert Rev Clin Pharmacol 2022; 15:1293-1304. [DOI: 10.1080/17512433.2022.2140656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Affiliation(s)
- Benjamin A. Teply
- Division of Hematology/Oncology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
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8
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Yu EY, Kolinsky MP, Berry WR, Retz M, Mourey L, Piulats JM, Appleman LJ, Romano E, Gravis G, Gurney H, Bögemann M, Emmenegger U, Joshua AM, Linch M, Sridhar S, Conter HJ, Laguerre B, Massard C, Li XT, Schloss C, Poehlein CH, de Bono JS. Pembrolizumab Plus Docetaxel and Prednisone in Patients with Metastatic Castration-resistant Prostate Cancer: Long-term Results from the Phase 1b/2 KEYNOTE-365 Cohort B Study. Eur Urol 2022; 82:22-30. [PMID: 35397952 DOI: 10.1016/j.eururo.2022.02.023] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 01/21/2022] [Accepted: 02/22/2022] [Indexed: 12/15/2022]
Abstract
BACKGROUND Patients with metastatic castration-resistant prostate cancer (mCRPC) frequently receive docetaxel after they develop resistance to abiraterone or enzalutamide and need more efficacious treatments. OBJECTIVE To evaluate the efficacy and safety of pembrolizumab plus docetaxel and prednisone in patients with mCRPC. DESIGN, SETTING, AND PARTICIPANTS The trial included patients with mCRPC in the phase 1b/2 KEYNOTE-365 cohort B study who were chemotherapy naïve and who experienced failure of or were intolerant to ≥4 wk of abiraterone or enzalutamide for mCRPC with progressive disease within 6 mo of screening. INTERVENTION Pembrolizumab 200 mg intravenously (IV) every 3 wk (Q3W), docetaxel 75 mg/m2 IV Q3W, and prednisone 5 mg orally twice daily. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary endpoints were safety, the prostate-specific antigen (PSA) response rate, and the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by blinded independent central review (BICR). Secondary endpoints included time to PSA progression; the disease control rate (DCR) and duration of response (DOR) according to RECIST v1.1 by BICR; ORR, DCR, DOR, and radiographic progression-free survival (rPFS) according to Prostate Cancer Working Group 3-modified RECIST v1.1 by BICR; and overall survival (OS). RESULTS AND LIMITATIONS Among 104 treated patients, 52 had measurable disease. The median time from allocation to data cutoff (July 9, 2020) was 32.4 mo, during which 101 patients discontinued treatment, 81 (78%) for disease progression. The confirmed PSA response rate was 34% and the confirmed ORR (RECIST v1.1) was 23%. Median rPFS and OS were 8.5 mo and 20.2 mo, respectively. Treatment-related adverse events (TRAEs) occurred in 100 patients (96%). Grade 3-5 TRAEs occurred in 46 patients (44%). Seven AE-related deaths (6.7%) occurred (2 due to treatment-related pneumonitis). Limitations of the study include the single-arm design and small sample size. CONCLUSIONS Pembrolizumab plus docetaxel and prednisone demonstrated antitumor activity in chemotherapy-naïve patients with mCRPC treated with abiraterone or enzalutamide for mCRPC. Safety was consistent with profiles for the individual agents. Further investigation is warranted. PATIENT SUMMARY We evaluated the efficacy and safety of the anti-PD-1 antibody pembrolizumab combined with the chemotherapy drug docetaxel and the steroid prednisone for patients with metastatic prostate cancer resistant to androgen deprivation therapy , and who never received chemotherapy. The combination showed antitumor activity and manageable safety in this patient population. This trial is registered on ClinicalTrials.gov as NCT02861573.
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Affiliation(s)
- Evan Y Yu
- Department of Medicine, Division of Oncology, University of Washington and Fred Hutchinson Cancer Research Center, G4-830, Seattle, WA, USA.
| | | | - William R Berry
- Department of Medical Oncology, Duke Cancer Center Cary, Cary, NC, USA
| | - Margitta Retz
- Department of Urology, Rechts der Isar Medical Center, Technical University of Munich, Munich, Germany
| | - Loic Mourey
- Department of Medical Oncology, Institut Universitaire du Cancer de Toulouse - Oncopole, Toulouse, France
| | - Josep M Piulats
- Department of Medical Oncology, Catalan Institute of Oncology, Barcelona, Spain
| | - Leonard J Appleman
- Department of Hematology/Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Emanuela Romano
- Department of Medical Oncology, Center for Cancer Immunotherapy, Institut Curie, Paris, France
| | - Gwenaelle Gravis
- Department of Medical Oncology, Institut Paoli Calmettes, Aix-Marseille Université, Marseille, France
| | - Howard Gurney
- Department of Medical Oncology, Macquarie University, Sydney, NSW, Australia
| | - Martin Bögemann
- Department of Urology, University Hospital Münster, Münster, Germany
| | - Urban Emmenegger
- Division of Medical Oncology, Odette Cancer Centre and Sunnybrook Research Institute, Toronto, ON, Canada
| | - Anthony M Joshua
- Department of Medical Oncology, Kinghorn Cancer Centre, St Vincent's Hospital, Sydney, NSW, Australia
| | - Mark Linch
- Department of Oncology, University College London Hospital and UCL Cancer Institute, London, UK
| | - Srikala Sridhar
- Cancer Clinical Research Unit, UHN Princess Margaret Cancer Centre, Toronto, ON, Canada
| | - Henry J Conter
- Department of Medical Oncology, University of Western Ontario, Brampton, ON, Canada
| | - Brigitte Laguerre
- Department of Medical Oncology, Centre Eugene Marquis, Rennes, France
| | - Christophe Massard
- Department of Drug Development, Gustave Roussy Cancer Campus and Université Paris-Sud, Villejuif, France; Department of Medical Oncology, Gustave Roussy Cancer Campus and Université Paris-Sud, Villejuif, France
| | - Xin Tong Li
- Department of Medical Oncology, Merck & Co., Inc., Kenilworth, NJ, USA
| | - Charles Schloss
- Department of Medical Oncology, Merck & Co., Inc., Kenilworth, NJ, USA
| | | | - Johann S de Bono
- Division of Clinical Studies, The Royal Marsden Hospital and The Institute of Cancer Research, London, UK
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Cabozantinib in combination with atezolizumab in patients with metastatic castration-resistant prostate cancer: results from an expansion cohort of a multicentre, open-label, phase 1b trial (COSMIC-021). Lancet Oncol 2022; 23:899-909. [DOI: 10.1016/s1470-2045(22)00278-9] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 04/20/2022] [Accepted: 04/21/2022] [Indexed: 12/30/2022]
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10
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Shayegan B, Wallis CJ, Malone S, Cagiannos I, Hamilton RJ, Ferrario C, Gotto GT, Basappa NS, Morgan SC, Fernandes R, Morash C, Niazi T, Noonan KL, Rendon R, Osborne B, Park-Wyllie L, Chan KF, Hotte SJ, Saad F. Real-world use of systemic therapies in men with metastatic castration resistant prostate cancer (mCRPC) in Canada. Urol Oncol 2022; 40:192.e1-192.e9. [DOI: 10.1016/j.urolonc.2022.01.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 01/11/2022] [Accepted: 01/15/2022] [Indexed: 11/27/2022]
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11
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Kolinsky MP, Niederhoffer KY, Kwan EM, Hotte SJ, Hamilou Z, Yip SM, Chi KN, Wyatt AW, Saad F. Considerations on the identification and management of metastatic prostate cancer patients with DNA repair gene alterations in the Canadian context. Can Urol Assoc J 2022; 16:132-143. [PMID: 34812730 PMCID: PMC9054340 DOI: 10.5489/cuaj.7621] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Olaparib is the first Health Canada-approved agent in metastatic prostate cancer to use a companion diagnostic to identify alterations in BRCA1, BRCA2, or ATM. As olaparib is introduced, clinicians must learn to access and interpret germline and somatic next-generation sequencing (NGS) results, and how to manage affected patients who appear to have distinct clinical features. The traditional model of referring patients to a hereditary cancer clinic (HCC) for germline testing is likely impractical in this disease, as the metastatic prostate cancer patient population would be overwhelming. Alternate approaches to this are clinician-ordered genetic testing (so-called “mainstreaming”), out-of-pocket payment for third-party private company genetic testing, or germline testing done in conjunction with somatic testing, particularly cell free circulating tumor DNA (ctDNA).
Germline testing alone is not sufficient for identifying Olaparib-eligible patients, as less than half of BRCA1, BRCA2, or ATM alterations are germline in origin, but it is critically important to identify family members who are carriers so that risk-reduction measures can be undertaken. Somatic testing is not widely available in Canada, but some patients can access it through research protocols or by paying out-of-pocket. Somatic testing can be performed on archival or fresh solid tissue biopsy samples, or through whole blood samples to access plasma-derived circulating tumor DNA (ctDNA). Both testing approaches have relative advantages and disadvantages, but neither may be informative in all patients and, therefore, ideal somatic NGS pathways should provide options for both tissue and ctDNA testing.
We advocate that clinicians begin discussions with their provincial lab formularies, HCC, and molecular pathology labs to highlight the importance of germline and somatic testing in this population and identify pathways for patient access. While olaparib has approval for use in BRCA1, BRCA2, and ATM-altered mCRPC, emerging evidence suggests that PARP inhibitors have variable activity in these three genes, with BRCA2 alterations appearing to be the most responsive. Retrospective and prospective series have reported varying outcomes to standard of care therapies, such as ARATs and taxane-based chemotherapy, in metastatic castration-resistant prostate cancer (mCRPC) patients with DNA damage repair (DDR) gene alterations, such as BRCA2. In the absence of high-level evidence showing a lack of benefit, we believe this patient population should still be considered for these treatments.
In addition, platinum-based chemotherapy appears to have activity in DDR gene-altered mCRPC and should be considered another option when access to olaparib is not possible.
At present, there is no evidence to support an optimal treatment sequence in this patient population, therefore, physician and patient preferences will need to be taken into consideration when selecting therapies. As olaparib and other PARP inhibitors are tested in different disease states and in combination with other therapies, we will likely see a more refined approach to use of these agents and management of this new biomarker-defined patient population.
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Affiliation(s)
- Michael P. Kolinsky
- Cross Cancer Institute, Edmonton, Alberta, Canada; Department of Oncology, University of Alberta, Edmonton, AB, Canada
| | | | - Edmond M. Kwan
- Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
| | | | - Zineb Hamilou
- Division of Oncology, Centre Hospitalier de l’Université de Montréal, Montreal, QC, Canada
| | - Steven M. Yip
- Tom Baker Cancer Centre and Cumming School of Medicine, Calgary, AB, Canada
| | - Kim N. Chi
- BC Cancer Agency and University of British Columbia, Vancouver, BC, Canada
| | - Alexander W. Wyatt
- Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia and Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada
| | - Fred Saad
- Centre Hospitalier de l’Université de Montréal, Université de Montréal, Montreal, QC, Canada
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12
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Orme JJ, Pagliaro LC, Quevedo JF, Park SS, Costello BA. Rational Second-Generation Antiandrogen Use in Prostate Cancer. Oncologist 2022; 27:110-124. [PMID: 35641216 PMCID: PMC8895732 DOI: 10.1093/oncolo/oyab045] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 10/04/2021] [Indexed: 12/18/2022] Open
Abstract
The second-generation antiandrogens have achieved an ever-growing list of approvals and indications in subsets of prostate cancer. Here, we provide an overview of second-generation antiandrogen trials and FDA approvals and outline a rational sequencing approach for the use of these agents as they relate to chemotherapy and other available treatment modalities in advanced prostate cancer. All published phase II-III randomized controlled trials reporting outcomes with the use of second-generation antiandrogens in prostate cancer are included as well as all published trials and retrospective studies of second-generation antiandrogen sequencing and/or combinations. Complete tabular and graphical representation of all available evidence is provided regarding the use and sequencing of second-generation antiandrogens in prostate cancer. In metastatic castration-resistant prostate cancer, evidence suggests prioritization of abiraterone before chemotherapy, chemotherapy after second-generation antiandrogen failure, and postchemotherapy enzalutamide in select patients to maximize agent efficacy and tolerability. We conclude that a rational, optimized sequencing of second-generation antiandrogens with other treatment options is feasible with present data.
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Affiliation(s)
- Jacob J Orme
- Division of Medical Oncology, Mayo Clinic, Rochester, MN, USA
| | | | | | - Sean S Park
- Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA
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Yang X, Chen H, Xu D, Chen X, Li Y, Tian J, Wang D, Pang J. Efficacy and safety of Androgen Deprivation Therapy (ADT) combined with modified docetaxel chemotherapy versus ADT combined with standard docetaxel chemotherapy in patients with metastatic castration-resistant prostate cancer: study protocol for a multicentre prospective randomized controlled trial. BMC Cancer 2022; 22:177. [PMID: 35172779 PMCID: PMC8848813 DOI: 10.1186/s12885-022-09276-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Accepted: 02/08/2022] [Indexed: 11/14/2022] Open
Abstract
Background Androgen deprivation therapy (ADT) combined with docetaxel chemotherapy is the standard treatment for metastatic castration-resistant prostate cancer (mCRPC) patients. However, mCRPC patients are mainly frail elderly men, constantly accompanied by comorbidities and showing poor tolerance to standard docetaxel chemotherapy. Some exploratory studies administering modified chemotherapy regimens have reported noninferior oncologic outcomes with fewer adverse events, yet most are retrospective or small studies, and prospective randomized controlled trials have rarely been conducted. Therefore, we designed this modified docetaxel chemotherapy regimen in patients with mCRPC, aiming to evaluate its efficacy and safety compared with the standard docetaxel chemotherapy regimen. Methods This is an open-label, multi-institutional, prospective, randomized non-inferiority trial. A total of 128 patients with mCRPC will be randomized to receive ADT combined with modified docetaxel chemotherapy (experimental group, n=64) or ADT combined with standard docetaxel chemotherapy (control group, n=64). Patients in the experimental group will receive a modified regimen with docetaxel 40 mg/m2 on the 1st day and 35 mg/m2 on the 8th day, repeated every 21 days. The primary endpoint is progression-free survival at 2 years. Secondary endpoints include overall survival, prostate-specific antigen response rate, pain response rate, toxicity and quality of life. Discussion The expected benefit for the patient in the experimental arm is noninferior efficacy with decreased toxicity and improved quality of life compared with that in the control arm. To the best of our knowledge, this will be the first multicentre prospective randomized study to assess the efficacy and safety of modified docetaxel chemotherapy in patients with mCRPC in China. The results of this trial may provide benefit to mCRPC patients, especially those with poor performance. Trial registration chictr.org.cn Identifier: ChiCTR2100046636 (May 24, 2021). Ongoing study.
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Affiliation(s)
- Xiangwei Yang
- Department of Urology, Kidney and Urology Center, Pelvic Floor Disorders Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Hong Chen
- School of Nursing, LKS Faculty of Medicine, University of Hong Kong, Hong Kong, China
| | - Duanya Xu
- Department of Urology, Kidney and Urology Center, Pelvic Floor Disorders Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Xianju Chen
- Department of Urology, Kidney and Urology Center, Pelvic Floor Disorders Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Yamei Li
- Department of Urology, Kidney and Urology Center, Pelvic Floor Disorders Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Jun Tian
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Dongwen Wang
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China.
| | - Jun Pang
- Department of Urology, Kidney and Urology Center, Pelvic Floor Disorders Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.
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14
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Naiki T, Takahara K, Ito T, Nakane K, Sugiyama Y, Koie T, Shiroki R, Miyake H, Yasui T. Comparison of clinical outcomes between androgen deprivation therapy with up-front abiraterone and bicalutamide for Japanese patients with LATITUDE high-risk prostate cancer in a real-world retrospective analysis. Int J Clin Oncol 2021; 27:592-601. [PMID: 34779958 DOI: 10.1007/s10147-021-02071-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Accepted: 11/02/2021] [Indexed: 11/25/2022]
Abstract
BACKGROUND Combining abiraterone (Abi) with androgen deprivation therapy (ADT) improves overall survival, compared to ADT only, in patients with metastatic castration-sensitive prostate cancer (mCSPC). In Japan, bicalutamide (Bica) and ADT (combined androgen blockade: CAB) is frequently provided for mCSPC. Because these two treatments have not been compared, mCSPC patients who received either treatment were retrospectively analyzed. METHODS Of 178 patients with LATITUDE high-risk mCSPC, 103 had received ADT plus upfront Abi (Abi group) and 75 had received ADT plus Bica (Bica group) in multiple institutions of the Tokai Urologic Oncology Research Seminar. Kaplan-Meir curves were used to retrospectively analyze survival and cancer recurrence. Univariate and multivariate Cox regression analyses identified potential prognostic factors for progression-free survival (PFS). RESULTS Significant differences in major clinicopathological characteristics between the two groups were not observed. The rate of castration-resistant development was higher in the Bica compared to Abi group (50.6 vs. 25.2%, p < 0.001). The median PFS in the Bica group was 13.6 months {95% confidence interval [CI] 9.2-22.2}; however, in the Abi group, PFS did not reach the median {95% CI 18.5-not assessed [NA]; p < 0.001}. Time to second progression for the Abi group was superior (p = 0.07). Univariate and multivariate analyses revealed Gleason pattern 5, high alkaline phosphatase levels, and conventional CAB using Bica as significant prognostic factors for short PFS. CONCLUSIONS In patients with LATITUDE high-risk mCSPC, upfront use of Abi combined with ADT resulted in favorable prognostic outcomes compared with conventional ADT with Bica.
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Affiliation(s)
- Taku Naiki
- Department of Nephro-urology, Graduate School of Medical Sciences, Nagoya City University, Kawasumi 1, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan.
| | | | - Toshiki Ito
- Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Keita Nakane
- Department of Urology, Gifu University, Gifu, Japan
| | - Yosuke Sugiyama
- Department of Nephro-urology, Graduate School of Medical Sciences, Nagoya City University, Kawasumi 1, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Takuya Koie
- Department of Urology, Gifu University, Gifu, Japan
| | - Ryoichi Shiroki
- Department of Urology, Fujita Medical University, Nagoya, Japan
| | - Hideaki Miyake
- Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Takahiro Yasui
- Department of Nephro-urology, Graduate School of Medical Sciences, Nagoya City University, Kawasumi 1, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
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15
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Shore ND, Ionescu-Ittu R, Laliberté F, Yang L, Lejeune D, Yu L, Duh MS, Mahendran M, Kim J, Ghate SR. Beyond Frontline Therapy with Abiraterone and Enzalutamide in Metastatic Castration-Resistant Prostate Cancer: A Real-World US Study. Clin Genitourin Cancer 2021; 19:480-490. [PMID: 34373223 DOI: 10.1016/j.clgc.2021.07.009] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 05/27/2021] [Accepted: 07/02/2021] [Indexed: 12/01/2022]
Abstract
BACKGROUND Real-world evidence suggest that next generation hormonal agents (NHAs) abiraterone and enzalutamide were preferred as first-line (1L) therapies for metastatic castration-resistant prostate cancer (mCRPC) in the United States (US) pre-2020, with chemotherapies, particularly docetaxel, being preferred in subsequent lines (2L+). This real-world study described patient characteristics, treatment patterns, time on treatment (ToT) and overall survival (OS) among patients with mCRPC treated with 2L and 3L docetaxel post-NHAs in the mCRPC setting. METHODS Adults with confirmed adenocarcinoma mCRPC diagnosis and ≥1 month of follow-up post-diagnosis were selected from a US electronic health record-derived oncology de-identified database (01/2013-03/2019). Based on the observed line of therapy sequences post-mCRPC diagnosis, patients who received NHA therapy in 1L and docetaxel therapy in 2L were included in the 2L docetaxel cohort, and patients who received NHA therapy in both 1L and 2L and docetaxel therapy in 3L were included in the 3L docetaxel cohort. ToT and OS were evaluated using Kaplan-Meier analysis. RESULTS Among 5,213 patients with mCRPC, 278 and 166 were included in the 2L and the 3L docetaxel cohorts, respectively (median age: 73 years for both cohorts). ADT was the most used class of medication pre-mCRPC (>75%). For the 2L cohort, the most common sequence post-mCRPC was 1L abiraterone → 2L docetaxel (52.5%), while the median ToT and OS post-2L start were 4.1 and 10.5 months, respectively; for the 3L cohort, the most common sequence post-mCRPC was 1L abiraterone → 2L enzalutamide → 3L docetaxel (67.5%), while the median ToT and OS post-3L start were 3.8 and 8.7 months, respectively. CONCLUSIONS This real-world study provides novel data on patients treated with docetaxel post-NHAs in a mCRPC setting and highlights the critical unmet need for developing more effective treatment options in this population.
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Affiliation(s)
- Neal D Shore
- Carolina Urologic Research Center, Myrtle Beach.
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16
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Pereira-Salgado A, Kwan EM, Tran B, Gibbs P, De Bono J, IJzerman M. Systematic Review of Efficacy and Health Economic Implications of Real-world Treatment Sequencing in Prostate Cancer: Where Do the Newer Agents Enzalutamide and Abiraterone Fit in? Eur Urol Focus 2021; 7:752-763. [PMID: 32273196 DOI: 10.1016/j.euf.2020.03.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 02/11/2020] [Accepted: 03/04/2020] [Indexed: 11/30/2022]
Abstract
CONTEXT Optimal treatment sequencing of abiraterone and enzalutamide in chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) is challenging. Real-world data (RWD) allow a better understanding of health economic implications in the real world. OBJECTIVE To determine survival and cost outcomes for two real-world treatment sequences, comparing abiraterone to enzalutamide (AA → ENZ) with enzalutamide to abiraterone (ENZ → AA). EVIDENCE ACQUISITION A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Searches were performed in Medline, Embase, and Web of Science. EVIDENCE SYNTHESIS Seventeen studies met our inclusion criteria. Of studies with survival outcomes, 10 featured AA → ENZ treatment sequences (n = 575), four ENZ → AA sequences (n = 205), and three both sequences. Better survival outcomes were demonstrated in the AA → ENZ cohorts in several studies reporting prostate-specific antigen (PSA) progression-free survival (PSA-PFS), combined PSA-PFS, and PSA decline ≥50%. Three studies showed shorter treatment duration in cohorts receiving second-line enzalutamide compared with abiraterone. Collectively, six RWD costing studies described patients with mCRPC who experienced treatment with enzalutamide (n = 4195), abiraterone (n = 10 372), AA → ENZ (n = 443), and ENZ → AA (n = 91). No study estimated the cost of treatment sequencing of AA → ENZ or ENZ → AA. CONCLUSIONS No head-to-head studies were found, but we hypothesise that the AA → ENZ sequence may be less costly than ENZ → AA, because time on treatment tends to be longer for a first-line treatment and abiraterone is less costly than enzalutamide. There are indications that PFS of AA → ENZ is superior to that of ENZ → AA, which supports the former sequence as more cost-effective. PATIENT SUMMARY Better survival outcomes were reported in several studies where patients with advanced prostate cancer received the abiraterone to enzalutamide sequence compared with the enzalutamide to abiraterone sequence. No study estimated the cost of sequencing either treatment approach.
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Affiliation(s)
- Amanda Pereira-Salgado
- Cancer Health Services Research, Centre for Health Policy, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne Centre for Cancer Research, Melbourne, VIC, Australia.
| | - Edmond Michael Kwan
- Department of Medicine, School of Clinical Sciences, Monash University, VIC, Australia; Department of Medical Oncology, Monash Health, VIC, Australia
| | - Ben Tran
- Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Personalised Oncology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
| | - Peter Gibbs
- Personalised Oncology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
| | - Johann De Bono
- Institute of Cancer Research, Royal Marsden Hospital, London, UK
| | - Maarten IJzerman
- Cancer Health Services Research, Centre for Health Policy, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne Centre for Cancer Research, Melbourne, VIC, Australia; Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Victorian Comprehensive Cancer Centre, VIC, Australia
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17
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Cross-resistance and drug sequence in prostate cancer. Drug Resist Updat 2021; 56:100761. [PMID: 33799049 DOI: 10.1016/j.drup.2021.100761] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 03/12/2021] [Accepted: 03/17/2021] [Indexed: 02/06/2023]
Abstract
The treatment landscape of advanced prostate cancer has widely expanded over the past years with androgen receptor signaling inhibitors (ARSIs) and taxane chemotherapy moving to earlier disease stages in the treatment of prostate cancer. With the increasing use of ARSIs in earlier disease stages, cross-resistance between treatments has emerged, which is a dominant impediment in current clinical practice. To overcome cross-resistance in the treatment of prostate cancer, it is of paramount importance to decipher the mechanisms of cross-resistance between ARSIs and between ARSIs and chemotherapy. Here, molecular mechanisms of resistance to the available therapies including androgen receptor (AR) splice variants, AR overexpression, AR mutations and glucocorticoid receptor upregulation are described. Based on these underlying mechanisms, clinical data of cross-resistance between ARSIs and chemotherapy have been reported. Only recently these data have been confirmed in prospective randomized trials. From these studies, it has become clear that sequential ARSI treatment has no place in the treatment of advanced prostate cancer due to emerging drug resistance. In addition, based on prospective evidence, we argue that it is worth considering an early switch to cabazitaxel treatment in case of lack of benefit on docetaxel regimen after an ARSI treatment. Based on these new insights from randomized trials, several recommendations for treatment sequence are proposed.
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18
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Kwon DH, Chou J, Yip SM, Reimers MA, Zhang L, Wright F, Dhawan MS, Borno HT, Desai A, Aggarwal RR, Wyatt AW, Small EJ, Alva AS, Chi KN, Feng FY, Koshkin VS. Differential treatment outcomes in BRCA1/2-, CDK12-, and ATM-mutated metastatic castration-resistant prostate cancer. Cancer 2021; 127:1965-1973. [PMID: 33690902 DOI: 10.1002/cncr.33487] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 12/01/2020] [Accepted: 01/19/2021] [Indexed: 11/10/2022]
Abstract
BACKGROUND DNA damage repair mutations (DDRm) are common in patients with metastatic castration-resistant prostate cancer (mCRPC). The optimal standard therapy for this population is not well described. METHODS A multi-institutional, retrospective study of patients with mCRPC and DDRm was conducted. Patient data, including systemic therapies and responses, were collected. The decline in prostate-specific antigen ≥ 50% from baseline (PSA50) and overall survival (OS) from the treatment start were compared by mutation and treatment type. A multivariable Cox proportional hazards model for OS was created that controlled for DDRm, first-line treatment received for mCRPC, and clinical factors. RESULTS The most common DDRm observed among 149 men with mCRPC were BRCA1/2 (44%), CDK12 (32%), and ATM (15%). The majority received first-line abiraterone (40%) or enzalutamide (30%). The PSA50 rate with first-line abiraterone was lower for CDK12 (52%) than BRCA1/2 (89%; P = .02). After first-line abiraterone or enzalutamide, the median OS was longest with second-line carboplatin-chemotherapy (38 months) in comparison with abiraterone or enzalutamide (33 months), docetaxel (17 months), or cabazitaxel (11 months; P = .02). PSA50 responses to carboplatin-based chemotherapy were higher for BRCA1/2 (79%) than ATM (14%; P = .02) or CDK12 (38%; P = .08). In a multivariable analysis, neither the specific DDRm type nor the first-line treatment was associated with improved OS. CONCLUSIONS Responses to standard therapies were generally superior in patients with BRCA1/2 mutations and inferior in patients with ATM or CDK12 mutations. The DDRm type did not independently predict OS. After progression on first-line abiraterone or enzalutamide, carboplatin-based chemotherapy was associated with the longest OS. These findings may inform treatment discussions and clinical trial design and require prospective validation.
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Affiliation(s)
- Daniel H Kwon
- Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, California
| | - Jonathan Chou
- Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, California
| | - Steven M Yip
- Tom Baker Cancer Centre, University of Calgary, Calgary, Alberta, Canada
| | - Melissa A Reimers
- Division of Oncology, Department of Medicine, Washington University, St. Louis, Missouri
| | - Li Zhang
- Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, California.,Department of Biostatistics and Epidemiology, University of California San Francisco, San Francisco, California
| | - Francis Wright
- Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, California
| | - Mallika S Dhawan
- Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, California
| | - Hala T Borno
- Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, California
| | - Arpita Desai
- Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, California
| | - Rahul R Aggarwal
- Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, California
| | - Alexander W Wyatt
- Vancouver Prostate Centre, Vancouver, British Columbia, Canada.,Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Eric J Small
- Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, California
| | - Ajjai S Alva
- Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
| | - Kim N Chi
- Vancouver Prostate Centre, Vancouver, British Columbia, Canada.,BC Cancer Agency, Vancouver, British Columbia, Canada
| | - Felix Y Feng
- Department of Radiation Oncology, University of California San Francisco, San Francisco, California
| | - Vadim S Koshkin
- Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, California
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19
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Cassinello J, Domínguez-Lubillo T, Gómez-Barrera M, Hernando T, Parra R, Asensio I, Casado MA, Moreno P. Optimal treatment sequencing of abiraterone acetate plus prednisone and enzalutamide in patients with castration-resistant metastatic prostate cancer: A systematic review and meta-analysis. Cancer Treat Rev 2021; 93:102152. [PMID: 33486302 DOI: 10.1016/j.ctrv.2020.102152] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 12/22/2020] [Accepted: 12/24/2020] [Indexed: 01/19/2023]
Abstract
PURPOSE To evaluate the impact of the hormonal treatment sequencing including abiraterone acetate plus prednisone (AAP) and enzalutamide (ENZ) in mCRPC, and determine which sequence provides more benefits for patients. METHODS Studies published in English between 1 January 2013 and 30 September 2017 were identified in PubMed and EMBASE electronic databases. Studies assessing the efficacy of treatment sequences, based on AAP and ENZ, in mCRPC patients, were eligible for analysis. RESULTS Seventeen studies met the inclusion criteria. Two assessed both treatment sequences AAP → ENZ and ENZ → AAP; it was found that sequence of AAP → ENZ showed a statistically significantly longer PSA-PFS than the observed in ENZ → AAP (pooled HR: 0,54; 95% CI; 0,36-0,82; p < 0,05). The nine studies analysing Doc → AAP → ENZ sequence, revealed favourable results in terms of PFS. The 5 studies which analysed AAP → ENZ sequence, show a decrease in PSA levels ≥ 50% in 11-41% of patients treated with enzalutamide after previous treatment with AAP. In the two studies that analysed the Doc → ENZ → AAP sequence, PSA response rates were much lower than those reported with Doc → AAP → ENZ, with decreases in PSA ≥ 30 of 3-18% and PSA ≥ 50 of 8-11%. CONCLUSION Significant clinical efficacy of AAP administered as the first-line treatment in mCRPC patients followed by enzalutamide, delaying disease progression, compared with the ENZ → AAP sequence. However, more studies and randomized trials are needed, to validate the best treatment sequencing.
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Affiliation(s)
- J Cassinello
- Department of Oncology, University General Hospital of Guadalajara, Calle Donante de Sangre, S/N, 19002, Guadalajara, Spain
| | - T Domínguez-Lubillo
- Department of health economics and market access, Janssen-Cilag, Paseo Doce Estrellas 5-7, 28042 Madrid, Spain
| | - M Gómez-Barrera
- Pharmacoeconomics & Outcomes Research Iberia (PORIB), Paseo Joaquín Rodrigo, 4 i, 28224, Pozuelo de Alarcón, Madrid, Spain
| | - T Hernando
- Department of health economics and market access, Janssen-Cilag, Paseo Doce Estrellas 5-7, 28042 Madrid, Spain
| | - R Parra
- Department of health economics and market access, Janssen-Cilag, Paseo Doce Estrellas 5-7, 28042 Madrid, Spain
| | - I Asensio
- Department of health economics and market access, Janssen-Cilag, Paseo Doce Estrellas 5-7, 28042 Madrid, Spain
| | - M A Casado
- Pharmacoeconomics & Outcomes Research Iberia (PORIB), Paseo Joaquín Rodrigo, 4 i, 28224, Pozuelo de Alarcón, Madrid, Spain
| | - P Moreno
- Department of health economics and market access, Janssen-Cilag, Paseo Doce Estrellas 5-7, 28042 Madrid, Spain.
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Hird AE, Magee DE, Cheung DC, Matta R, Kulkarni GS, Nam RK. Abiraterone vs. docetaxel for metastatic hormone-sensitive prostate cancer: A microsimulation model. Can Urol Assoc J 2020; 14:E418-E427. [PMID: 32223875 PMCID: PMC7492043 DOI: 10.5489/cuaj.6234] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
INTRODUCTION Our aim was to determine whether androgen deprivation therapy (ADT) with abiraterone acetate (AA) or ADT with docetaxel chemotherapy (DC) resulted in improved quality-adjusted life years (QALYs) among men with de novo metastatic castration-sensitive prostate cancer (mCSPC) and the cost effectiveness of the preferred strategy using decision analytic techniques. METHODS A microsimulation model with a lifetime time horizon was constructed. Our primary outcome was QALYs. Secondary outcomes included cost, incremental cost effectiveness ratio (ICER), unadjusted overall survival (OS), rates of second- and third-line therapy, and adverse events. A systematic literature review was used to generate probabilities and utilities to populate the model. The base case was a 65-year-old patient with de novo mCSPC. RESULTS A total of 100 000 microsimulations were generated. Initial AA resulted in a gain of 0.45 QALYs compared to DC (3.36 vs. 2.91 QALYs) with an ICER of $276 251.82 per QALY gained with initial AA therapy. Median crude OS was 51 months with AA and 48 months with DC. Overall, 46.6% and 42.6% of patients received second-line therapy and 8.7% and 7.9% patients received third-line therapy in the AA and DC groups, respectively. Grade 3/4 adverse events were experienced in 17.6% of patients receiving initial AA and 22.3% of patients receiving initial DC. CONCLUSIONS Although ADT with AA results in a gain in QALYs and crude OS compared to DC, AA therapy is not a cost-effective treatment strategy to apply uniformly to all patients. The availability of AA as a generic medication may help to close this gap. The ultimate choice should be based on patient and tumor factors.
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Affiliation(s)
- Amanda E. Hird
- Division of Urology, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
- Institute for Health Policy, Management, and Evaluation, University of Toronto, Toronto, ON, Canada
| | - Diana E. Magee
- Institute for Health Policy, Management, and Evaluation, University of Toronto, Toronto, ON, Canada
- Division of Urology, Princess Margaret Hospital, University Health Network, Toronto, ON, Canada
| | - Douglas C. Cheung
- Institute for Health Policy, Management, and Evaluation, University of Toronto, Toronto, ON, Canada
- Division of Urology, Princess Margaret Hospital, University Health Network, Toronto, ON, Canada
| | - Rano Matta
- Division of Urology, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
- Institute for Health Policy, Management, and Evaluation, University of Toronto, Toronto, ON, Canada
| | - Girish S. Kulkarni
- Institute for Health Policy, Management, and Evaluation, University of Toronto, Toronto, ON, Canada
- Division of Urology, Princess Margaret Hospital, University Health Network, Toronto, ON, Canada
| | - Robert K. Nam
- Division of Urology, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
- Institute for Health Policy, Management, and Evaluation, University of Toronto, Toronto, ON, Canada
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21
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Affiliation(s)
| | | | - Paz Polak
- Icahn School of Medicine at Mount Sinai, New York, NY
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22
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Gacci M, Marchioni M, DE Francesco P, Natoli C, Calabrò F, Losanno T, Gianmartin C, Serni S, Doni L, DE Nunzio C, DE Tursi M, Valeriani M, Giacinti S, Álvarez-Maestro M, Scarcia M, Ludovico GM, Del Bene G, Simone G, Ferriero M, Tuderti G, Bove P, Laudisi A, Carrieri G, Cormio L, Verze P, LA Rocca R, Falsaperla M, Frantellizzi V, Greco F, DI Nicola M, Schips L, Cindolo L. Enzalutamide in patients with castration-resistant prostate cancer: retrospective, multicenter, real life study. Minerva Urol Nephrol 2020; 73:489-497. [PMID: 32748613 DOI: 10.23736/s2724-6051.20.03723-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND Metastatic castration-resistant prostate cancer (mCRPC) is the final stage of pCa history and represents a clinically relevant phenotype with an elevated burden of mortality. The aim of the present study was to evaluate the efficacy and safety of enzalutamide in a "real-life" setting in mCRPC patients. METHODS Data about all mCRPC patients treated with enzalutamide from September 2017 to September 2018 were collected. Demographics, comorbidities, clinical parameters, outcomes, toxicity, overall survival and progression free survival were analyzed. RESULTS Overall, 158 patients were enrolled. Mean age was 75.8 (±8.7) years with a baseline median PSA of 16.5 (IQR 7.4-47.8) ng/mL. The median follow-up lasted 7.7 (IQR 4-14.1) months. Of all the 10.1% of patients reported grade 3-4 adverse events. 43.7% of patients experienced a progression. Overall, the 6 and 12 months PFS rates were 69.5% (95% CI: 61.7-78.3%) and the 45.6% (95% CI: 36.5-57.1%); a median baseline PSA>16 ng/mL (HR:2.0, 95% CI: 1.2-3.3, P<0.005), the use of opioid (HR: 3.1, 95% CI: 1.9-5.0, P<0.001), a previous treatment (abiraterone, docetaxel or abiraterone + docetaxel) were significantly associated with higher rates of cancer progression. Conversely, a brief pain questionnaire of 0-1 (HR: 0.4, 95% CI: 0.2-0.7, P<0.001), a 12 weeks 50% PSA reduction (HR: 0.4, 95% CI: 0.2-0.8, P<0.006) and a longer time to mCRPC (HR: 0.4, 95% CI: 0.3-0.7, P<0.002) were related to lower cancer progression rates. CONCLUSIONS Our data shows an effective and safe profile of enzalutamide in a "real world" perspective in patients with mcRPC.
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Affiliation(s)
- Mauro Gacci
- Department of Minimally Invasive and Robotic Urologic Surgery and Kidney Transplantation, AOUC Careggi Hospital, Florence, Italy
| | - Michele Marchioni
- Department of Medical, Oral and Biotechnological Sciences, Laboratory of Biostatistics, G. D'Annunzio University, Chieti, Chieti-Pescara, Italy
| | | | - Clara Natoli
- Department of Medical, Oral and Biotechnological Sciences, Medical Oncology, G. D'Annunzio University, Chieti, Chieti-Pescara, Italy
| | - Fabio Calabrò
- Department of Medical Oncology, San Camillo-Forlanini Hospital, Rome, Italy
| | - Tania Losanno
- Department of Medical Oncology, San Camillo-Forlanini Hospital, Rome, Italy
| | - Cito Gianmartin
- Department of Minimally Invasive and Robotic Urologic Surgery and Kidney Transplantation, AOUC Careggi Hospital, Florence, Italy
| | - Sergio Serni
- Department of Minimally Invasive and Robotic Urologic Surgery and Kidney Transplantation, AOUC Careggi Hospital, Florence, Italy
| | - Laura Doni
- Department of Medical Oncology, Careggi University Hospital, Florence, Italy
| | - Cosimo DE Nunzio
- Department of Urology, Sant'Andrea Hospital, Sapienza University, Rome, Italy
| | - Michele DE Tursi
- Department of Medical, Oral and Biotechnological Sciences, Medical Oncology, G. D'Annunzio University, Chieti, Chieti-Pescara, Italy
| | - Maurizio Valeriani
- Unit of Radiation Therapy, Sant'Andrea Hospital, Sapienza University, Rome, Italy
| | - Silvana Giacinti
- Unit of Oncology, Sant'Andrea Hospital, Sapienza University, Rome, Italy
| | | | | | | | - Gabriella Del Bene
- Department of Medical Oncology, San Camillo-Forlanini Hospital, Rome, Italy
| | - Giuseppe Simone
- Department of Urology, Regina Elena National Cancer Institute, Rome, Italy
| | | | - Gabriele Tuderti
- Department of Urology, Regina Elena National Cancer Institute, Rome, Italy
| | - Pierluigi Bove
- Department of Experimental Medicine and Surgery, Tor Vergata Polyclinic, Rome, Italy.,Unit of Urology, San Carlo di Nancy Hospital, Rome, Italy
| | | | | | - Luigi Cormio
- Department of Urology, University of Foggia, Foggia, Italy
| | - Paolo Verze
- Unit of Urology, Department of Neurosciences, Sciences of Reproduction and Odontostomatology, Federico II University, Naples, Italy
| | - Roberto LA Rocca
- Unit of Urology, Department of Neurosciences, Sciences of Reproduction and Odontostomatology, Federico II University, Naples, Italy
| | - Mario Falsaperla
- Department of Urology, Vittorio Emanuele Polyclinic, Catania, Italy
| | | | - Francesco Greco
- Department of Urology, Humanitas Gavazzeni Hospital, Bergamo, Italy
| | - Marta DI Nicola
- Department of Medical, Oral and Biotechnological Sciences, Laboratory of Biostatistics, G. D'Annunzio University, Chieti, Chieti-Pescara, Italy
| | - Luigi Schips
- Department of Urology, ASL Abruzzo2, Chieti, Italy.,Department of Medical, Oral and Biotechnological Sciences, Department of Urology, G. D'Annunzio University, Chieti, Chieti-Pescara, Italy
| | - Luca Cindolo
- Department of Urology, ASL Abruzzo2, Chieti, Italy -
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Moussa M, Papatsoris A, Abou Chakra M, Sryropoulou D, Dellis A. Pharmacotherapeutic strategies for castrate-resistant prostate cancer. Expert Opin Pharmacother 2020; 21:1431-1448. [PMID: 32469248 DOI: 10.1080/14656566.2020.1767069] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
INTRODUCTION Metastatic castration-resistant prostate cancer (CRPC) is a potentially symptomatic disease with an eventual lethal outcome. Novel pharmaceutical agents are continuously studied with encouraging results in CRPC. AREAS COVERED In this perspective, the authors present established and promising pharmacotherapeutic strategies for the management of CRPC; both with and without metastases. Apart from the different treatment strategies, the authors present the relevant sequence of treatment through disease progression. EXPERT OPINION Usually, docetaxel should be considered the first line treatment in mCRPC. Abiraterone acetate (AA) plus prednisone or enzalutamide (ENZ) could be alternative treatments in chemotherapy naïve patients. Sipuleucel-T has been approved for the treatment of asymptomatic or minimally symptomatic mCRPC. Ra-223 has been approved for patients with mCRPC with symptomatic bone metastases (not visceral metastases). Cabazitaxel has been approved as the second line treatment to docetaxel in mCRPC. No differences in the overall survival has been observed between sequences starting with docetaxel versus AA/ENZ. Between AA-to-ENZ and ENZ-to-AA sequence, the AA-to-ENZ sequence appeared to be more favorable than the ENZ-to-AA regarding progression-free survival but not overall survival. Carbazitaxel seemed to retain its activity regardless of the treatment sequence. Of note, ENZ and apalutamide have been approved in non-metastatic CRPC.
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Affiliation(s)
- Mohamad Moussa
- Department of Urology, Al Zahraa Hospital, University Medical Center, Lebanese University , Beirut, Lebanon
| | - Athanasios Papatsoris
- 2nd Department of Urology, School of Medicine, Sismanoglio Hospital, National and Kapodistrian University of Athens , Athens, Greece
| | - Mohamed Abou Chakra
- Department of Urology, Al Zahraa Hospital, University Medical Center, Lebanese University , Beirut, Lebanon
| | | | - Athanasios Dellis
- 2nd Department of Urology, School of Medicine, Sismanoglio Hospital, National and Kapodistrian University of Athens , Athens, Greece.,Department of Surgery, School of Medicine, Aretaieion Hospital, National and Kapodistrian University of Athens , Athens
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Assi T, Rassy E, Farhat F, Kattan C, Kattan J. Docetaxel Rechallenge in Patients with Metastatic Prostate Cancer: A Comprehensive Review. Oncol Res Treat 2020; 43:299-306. [PMID: 32380503 DOI: 10.1159/000506693] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Accepted: 02/19/2020] [Indexed: 11/19/2022]
Abstract
BACKGROUND Recent years have witnessed a huge shift in the management and prognosis of metastatic prostate cancer with the advent of new-generation anti-hormonal treatments. Docetaxel, which was initially approved in the castrate-resistant prostate cancer setting, has been approved in the earlier course of the disease as it is still castrate sensitive. SUMMARY Apart from cabazitaxel and in the absence of other effective chemotherapies, docetaxel rechallenge (DR) in patients with proved sensitivity to docetaxel in the earlier stage of the disease remains a possible option. Unfortunately, the pivotal trials rarely reported on the outcomes of docetaxel retreatment which seems a plausible option in patients initially responding to docetaxel and maintaining a minimum progression-free interval of 3-6 months. In this review, a summary of the clinical evidence and potential concerns for the use of DR in patients with metastatic prostate cancer will be presented. Key Messages: Pivotal trials of docetaxel in metastatic castrate-sensitive prostate cancer as well as metastatic castrate-resistant prostate cancer have not reported on the outcomes of DR except in the GETUG-AFU 15 trial where the outcomes were disappointing. Based on the published retrospective data, DR may be effective in patients who initially responded to docetaxel and maintained a progression-free interval exceeding 6 months.
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Affiliation(s)
- Tarek Assi
- Department of Oncology, Faculty of Medicine, Saint Joseph University, Beirut, Lebanon, .,Oncology Department, Hammoud Hospital UMC, Saida, Lebanon,
| | - Elie Rassy
- Department of Oncology, Faculty of Medicine, Saint Joseph University, Beirut, Lebanon
| | - Fadi Farhat
- Department of Oncology, Faculty of Medicine, Saint Joseph University, Beirut, Lebanon.,Oncology Department, Hammoud Hospital UMC, Saida, Lebanon
| | - Clarisse Kattan
- Department of Oncology, Faculty of Medicine, Saint Joseph University, Beirut, Lebanon
| | - Joseph Kattan
- Department of Oncology, Faculty of Medicine, Saint Joseph University, Beirut, Lebanon
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Managing lines of therapy in castration-resistant prostate cancer: real-life snapshot from a multicenter cohort. World J Urol 2019; 38:1757-1764. [PMID: 31605196 DOI: 10.1007/s00345-019-02974-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Accepted: 09/27/2019] [Indexed: 01/26/2023] Open
Abstract
PURPOSE To provide a snapshot of toxicities and oncologic outcomes of Abiraterone (AA) and Enzalutamide (EZ) in a chemo-naïve metastatic castration-resistant prostate cancer (mCPRC) population from a longitudinal real-life multicenter cohort. METHODS We prospectively collected data on chemo-naïve mCRPC patients treated with AA or EZ. Primary outcomes were PSA response, oncologic outcomes and toxicity profile. The Kaplan-Meier method was used to compare differences in terms of progression-free survival (PFS) between AA vs EZ and high- vs low-volume disease cohorts. Univariable and multivariable Cox regression analyses were performed to identify predictors of PFS. Toxicity, PSA response rates and oncologic outcomes on second line were compared with those observed on first line. RESULTS Out of 137 patients, 88 received AA, and 49 EZ. On first line, patients receiving EZ had significantly higher PSA response compared with AA (95.9% vs 67%, p < 0.001), comparable toxicity rate (10.2% vs 16.3%, p = 0.437) and PFS probabilities (p = 0.145). Baseline PSA and high-volume disease were predictors of lower PFS probabilities at univariable analysis (p = 0.027 and p = 0.007, respectively). Overall, 28 patients shifted to a second-line therapy (EZ or radiometabolic therapy). Toxicity and PSA response rates on second line were comparable to those observed on first line (11.1% vs 12.4%, p = 0.77; 73.1% vs 77.4%, p = 0.62, respectively); 2-year PFS, cancer-specific and overall survival probabilities were comparable to those displayed in first-line cohort (12.1% vs 16.2%, p = 0.07; 85.7% vs 86.4%, p = 0.98; 71% vs 80.3%, p = 0.66, respectively). CONCLUSIONS Toxicity profile, PSA response rate and oncological outcomes were comparable between first-line and second-line courses in patients treated with either AA or EZ for mCRPC. Our findings showed the tolerability and oncological effectiveness, when feasible, of two lines of therapy other than chemotherapy.
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26
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Lee GT, Rosenfeld JA, Kim WT, Kwon YS, Palapattu G, Mehra R, Kim WJ, Kim IY. TCF4 induces enzalutamide resistance via neuroendocrine differentiation in prostate cancer. PLoS One 2019; 14:e0213488. [PMID: 31536510 PMCID: PMC6752758 DOI: 10.1371/journal.pone.0213488] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Accepted: 08/17/2019] [Indexed: 12/21/2022] Open
Abstract
In treating patients with castration resistant prostate cancer (CRPC), enzalutamide, the second-generation androgen receptor (AR) antagonist, is an accepted standard of care. However, clinical benefits are limited to a median time of 4.8 months because resistance inevitably emerges. To determine the mechanism of treatment resistance, we carried out a RNA sequence analysis and found increased expression levels of neuroendocrine markers in the enzalutamide-resistant LNCaP human prostate cancer (CaP) cell line when compared to the parental cell line. Subsequent studies demonstrated that Transcription Factor-4 (TCF4), a transcription factor implicated in WNT signaling, mediated neuroendocrine differentiation (NED) in response to enzalutamide treatment and was elevated in the enzalutamide-resistant LNCaP. In addition, we observed that PTHrP mediated enzalutamide resistance in tissue culture and inducible TCF4 overexpression resulted in enzalutamide-resistance in a mouse xenograft model. Finally, small molecule inhibitors of TCF4 or PTHrP partially reversed enzalutamide resistance in CaP cells. When tissues obtained from men who died of metastatic CaP were examined, a positive correlation was found between the expression levels of TCF4 and PTHrP. Taken together, the current results indicate that TCF4 induces enzalutamide resistance via NED in CaP.
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Affiliation(s)
- Geun Taek Lee
- Section of Urologic Oncology, Rutgers Cancer Institute of New Jersey, and Division of Urology, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, United States of America
| | - Jeffrey A. Rosenfeld
- Section of Urologic Oncology, Rutgers Cancer Institute of New Jersey, and Division of Urology, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, United States of America
| | - Won Tae Kim
- Section of Urologic Oncology, Rutgers Cancer Institute of New Jersey, and Division of Urology, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, United States of America
- Department of Urology, Chungbuk National University College of Medicine, Cheongju, Korea
| | - Young Suk Kwon
- Section of Urologic Oncology, Rutgers Cancer Institute of New Jersey, and Division of Urology, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, United States of America
| | - Ganesh Palapattu
- Department of Urology, University of Michigan, Ann Arbor, MI, United States of America
| | - Rohit Mehra
- Department of Urology, University of Michigan, Ann Arbor, MI, United States of America
| | - Wun-Jae Kim
- Department of Urology, Chungbuk National University College of Medicine, Cheongju, Korea
| | - Isaac Yi Kim
- Section of Urologic Oncology, Rutgers Cancer Institute of New Jersey, and Division of Urology, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, United States of America
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27
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Turk M, Simončič U, Roth A, Valentinuzzi D, Jeraj R. Computational modelling of resistance and associated treatment response heterogeneity in metastatic cancers. Phys Med Biol 2019; 64:115001. [PMID: 30790781 DOI: 10.1088/1361-6560/ab0924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Metastatic cancer patients invariably develop treatment resistance. Different levels of resistance lead to observed heterogeneity in treatment response. The main goal was to evaluate treatment response heterogeneity with a computation model simulating the dynamics of drug-sensitive and drug-resistant cells. Model parameters included proliferation, drug-induced death, transition and proportion of intrinsically resistant cells. The model was benchmarked with imaging metrics extracted from 39 metastatic prostate cancer patients who had 18F-NaF-PET/CT scans performed at baseline and at three cycles into chemotherapy or hormonal therapy. Two initial model assumptions were evaluated: considering only inter-patient heterogeneity and both inter-patient and intra-patient heterogeneity in the proportion of intrinsically resistant cells. The correlation between the median proportion of intrinsically resistant cells and baseline patient-level imaging metrics was assessed with Spearman's rank correlation coefficient. The impact of model parameters on simulated treatment response was evaluated with a sensitivity study. Treatment response after periods of six, nine, and 12 months was predicted with the model. The median predicted range of response for patients treated with both therapies was compared with a Wilcoxon rank sum test. For each patient, the time was calculated when the proportion of disease with a non-favourable response outperformed a favourable response. By taking into account inter-patient and intra-patient heterogeneity in the proportion of intrinsically resistant cells, the model performed significantly better ([Formula: see text]) than by taking into account only inter-patient heterogeneity ([Formula: see text]). The median proportion of intrinsically resistant cells showed a moderate correlation (ρ = 0.55) with mean patient-level uptake, and a low correlation (ρ = 0.36) with the dispersion of mean metastasis-level uptake in a patient. The sensitivity study showed a strong impact of the proportion of intrinsically resistant cells on model behaviour after three cycles of therapy. The difference in the median range of response (MRR) was not significant between cohorts at any time point (p > 0.15). The median time when the proportion of disease with a non-favourable response outperformed the favourable response was eight months, for both cohorts. The model provides an insight into inter-patient and intra-patient heterogeneity in the evolution of treatment resistance.
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Affiliation(s)
- Maruša Turk
- Faculty of Mathematics and Physics, University of Ljubljana, Ljubljana, Slovenia. Author to whom any correspondence should be addressed
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Prognostic Value of 18F-Fluorocholine PET Parameters in Metastatic Castrate-Resistant Prostate Cancer Patients Treated with Docetaxel. CONTRAST MEDIA & MOLECULAR IMAGING 2019; 2019:4325946. [PMID: 31049043 PMCID: PMC6458948 DOI: 10.1155/2019/4325946] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Accepted: 02/19/2019] [Indexed: 12/28/2022]
Abstract
Background and Aim The availability of new treatments for metastatic castrate-resistant prostate cancer (mCRPC) patients increases the need for reliable biomarkers to help clinicians to choose the better sequence strategy. The aim of the present retrospective and observational work is to investigate the prognostic value of 18F-fluorocholine (18F-FCH) positron emission tomography (PET) parameters in mCRPC. Materials and Methods Between March 2013 and August 2016, 29 patients with mCRPC were included. They all received three-weekly docetaxel after androgen deprivation therapy, and they underwent 18F-FCH PET/computed tomography (CT) before and after the therapy. Semi-quantitative indices such as maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean) with partial volume effect (PVC-SUV) correction, metabolically active tumour volume (MATV), and total lesion activity (TLA) with partial volume effect (PVC-TLA) correction were measured both in pre-treatment and post-treatment 18F-FCH PET/CT scans for each lesion. Whole-body indices were calculated as sum of values measured for each lesion (SSUVmax, SPVC-SUV, SMATV, and STLA). Progression-free survival (PFS) and overall survival (OS) were considered as clinical endpoints. Univariate and multivariate hazard ratios for whole-body 18F-FCH PET indices were performed, and p < 0.05 was considered as significant. Results Cox regression analysis showed a statistically significant correlation between PFS, SMATV, and STLA. No correlations between OS and 18F-FCH PET parameters were defined probably due to the small sample size. Conclusions Semi-quantitative indices such as SMATV and STLA at baseline have a prognostic role in patients treated with docetaxel for mCRPC, suggesting a potential role of 18F-FCH PET/CT imaging in clinical decision-making.
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Linder S, van der Poel HG, Bergman AM, Zwart W, Prekovic S. Enzalutamide therapy for advanced prostate cancer: efficacy, resistance and beyond. Endocr Relat Cancer 2018; 26:R31-R52. [PMID: 30382692 PMCID: PMC6215909 DOI: 10.1530/erc-18-0289] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/14/2018] [Indexed: 12/20/2022]
Abstract
The androgen receptor drives the growth of metastatic castration-resistant prostate cancer. This has led to the development of multiple novel drugs targeting this hormone-regulated transcription factor, such as enzalutamide – a potent androgen receptor antagonist. Despite the plethora of possible treatment options, the absolute survival benefit of each treatment separately is limited to a few months. Therefore, current research efforts are directed to determine the optimal sequence of therapies, discover novel drugs effective in metastatic castration-resistant prostate cancer and define patient subpopulations that ultimately benefit from these treatments. Molecular studies provide evidence on which pathways mediate treatment resistance and may lead to improved treatment for metastatic castration-resistant prostate cancer. This review provides, firstly a concise overview of the clinical development, use and effectiveness of enzalutamide in the treatment of advanced prostate cancer, secondly it describes translational research addressing enzalutamide response vs resistance and lastly highlights novel potential treatment strategies in the enzalutamide-resistant setting.
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Affiliation(s)
- Simon Linder
- Division of OncogenomicsOncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Henk G van der Poel
- Division of UrologyThe Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Andries M Bergman
- Division of Medical OncologyThe Netherlands Cancer Institute, Amsterdam, The Netherlands
- Division of OncogenomicsThe Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Wilbert Zwart
- Division of OncogenomicsOncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
- Laboratory of Chemical Biology and Institute for Complex Molecular SystemsDepartment of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands
| | - Stefan Prekovic
- Division of OncogenomicsOncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
- Correspondence should be addressed to S Prekovic:
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30
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Ingrosso G, Detti B, Scartoni D, Lancia A, Giacomelli I, Baki M, Carta G, Livi L, Santoni R. Current therapeutic options in metastatic castration-resistant prostate cancer. Semin Oncol 2018; 45:303-315. [PMID: 30446166 DOI: 10.1053/j.seminoncol.2018.10.001] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Revised: 07/30/2018] [Accepted: 10/15/2018] [Indexed: 11/11/2022]
Abstract
BACKGROUND The tumors of many patients with prostate cancer eventually become refractory to androgen deprivation therapy with progression to metastatic castration-resistant disease. Significant advances in the treatment of metastatic castration-resistant prostate cancer (mCRPC) have been made in recent years, and new treatment strategies have recently been made available. The aim of this report was to schematically review all the approved pharmacologic treatment options for patients with mCRPC through 2018, analyzing the efficacy and possible side effects of each therapy to assist clinicians in reaching an appropriate treatment decision. New biomarkers potentially of aid in the choice of treatment in this setting are also briefly reviewed. METHODS We performed a literature search of clinical trials of new drugs and treatments for patients diagnosed with mCRPC published through 2018. RESULTS Two new hormonal drugs, abiraterone acetate and enzalutamide have been approved by FDA in 2011 and 2012, respectively for the treatment of patients with mCRPC and have undergone extensive testing. While these treatments have shown a benefit in progression-free and overall survival, the appropriate sequencing must still be determined so that treatment decisions can be made based on their specific clinical profile. Cabazitaxel has been shown to be an efficient therapeutic option in a postdocetaxel setting, while its role in chemotherapy-naïve patients must still be determined. Sipuleucel-T and radium-223 have been studied in patients without visceral metastases and have achieved overall survival benefits with good safety profiles. The feasibility and efficacy of combinations of new treatments with other known therapies such as chemotherapy are currently under investigation. CONCLUSIONS Drug development efforts continue to attempt to prolong survival and improve quality of life in the mCRPC setting, with several therapeutic options available. Ongoing and future trials are needed to further assess the efficacy and safety of these new drugs and their interactions, along with the most appropriate sequencing.
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Affiliation(s)
- Gianluca Ingrosso
- Department of Diagnostic Imaging, Molecular Imaging, Interventional Radiology and Radiotherapy, Tor Vergata General Hospital, Rome, Italy
| | - Beatrice Detti
- Unit of Radiation Oncology, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy.
| | - Daniele Scartoni
- Unit of Radiation Oncology, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy
| | - Andrea Lancia
- Department of Diagnostic Imaging, Molecular Imaging, Interventional Radiology and Radiotherapy, Tor Vergata General Hospital, Rome, Italy
| | - Irene Giacomelli
- Unit of Radiation Oncology, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy
| | - Muhammed Baki
- Unit of Radiation Oncology, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy
| | - Giulio Carta
- Unit of Radiation Oncology, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy
| | - Lorenzo Livi
- Unit of Radiation Oncology, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy
| | - Riccardo Santoni
- Department of Diagnostic Imaging, Molecular Imaging, Interventional Radiology and Radiotherapy, Tor Vergata General Hospital, Rome, Italy
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Yadav S, Kowolik CM, Lin M, Zuro D, Hui SK, Riggs AD, Horne DA. SMC1A is associated with radioresistance in prostate cancer and acts by regulating epithelial-mesenchymal transition and cancer stem-like properties. Mol Carcinog 2018; 58:113-125. [PMID: 30242889 DOI: 10.1002/mc.22913] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Revised: 08/31/2018] [Accepted: 09/16/2018] [Indexed: 12/24/2022]
Abstract
Prostate cancer is one of the most commonly diagnosed cancers and a pressing health challenge in men worldwide. Radiation therapy (RT) is widely considered a standard therapy for advanced as well as localized prostate cancer. Although this primary therapy is associated with high cancer control rates, up to one-third of patients undergoing radiation therapy becomes radio-resistant and/or has tumor-relapse/recurrence. Therefore, focus on new molecular targets and pathways is essential to develop novel radio-sensitizing agents for the effective and safe treatment of prostate cancer. Here, we describe functional studies that were performed to investigate the role of structural maintenance of chromosome-1 (SMC1A) in radioresistance of metastatic prostate cancer cells. Short hairpin RNA (shRNA) was used to suppress SMC1A in metastatic castration-resistant prostate cancer cells, DU145 and PC3. Clonogenic survival assays, Western blot, RT-PCR, and γ-H2AX staining were used to assess the effect of SMC1A knockdown on radiation sensitivity of these prostate cancer cells. We demonstrate that SMC1A is overexpressed in human prostate tumors compared to the normal adjacent tissue. SMC1A knockdown limits the clonogenic potential, epithelial-mesenchymal transition (EMT), and cancer stem-like cell (CSC) properties of DU145 and PC3 cells and enhanced efficacy of RT in these cells. Targeted inhibition of SMC1A not only plays a critical role in overcoming radio-resistance in prostate cancer cells, but also suppresses self-renewal and the tumor-propagating potential of x-irradiated cancer cells. We propose that SMC1A could be a potential molecular target for the development of novel radio-sensitizing therapeutic agents for management of radio-resistant metastatic prostate cancer.
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Affiliation(s)
- Sushma Yadav
- Department of Translational Research and Cellular Therapeutics, City of Hope National Medical Center, Duarte, California.,Department of Molecular Medicine, City of Hope National Medical Center, Duarte, California
| | - Claudia M Kowolik
- Department of Molecular Medicine, City of Hope National Medical Center, Duarte, California
| | - Min Lin
- Department of Molecular Medicine, City of Hope National Medical Center, Duarte, California
| | - Darren Zuro
- Department of Radiation Oncology, City of Hope National Medical Center, Duarte, California
| | - Susanta K Hui
- Department of Radiation Oncology, City of Hope National Medical Center, Duarte, California
| | - Arthur D Riggs
- Diabetes and Metabolism Research Institute, City of Hope National Medical Center, Duarte, California
| | - David A Horne
- Department of Molecular Medicine, City of Hope National Medical Center, Duarte, California
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Survival Outcomes, Prostate-specific Antigen Response, and Tolerance in First and Later Lines of Enzalutamide Treatment for Metastatic Castration-resistant Prostate Cancer: A Real-World Experience in Hong Kong. Clin Genitourin Cancer 2018; 16:402-412.e1. [PMID: 30126765 DOI: 10.1016/j.clgc.2018.07.008] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 07/10/2018] [Accepted: 07/14/2018] [Indexed: 11/23/2022]
Abstract
BACKGROUND The present study retrospectively evaluated the efficacy and safety of enzalutamide in different lines of metastatic castration-resistant prostate cancer (mCRPC) treatment in a real-world setting. PATIENTS AND METHODS The clinical records of patients with mCRPC treated with enzalutamide between August 2015 and October 2017 were retrieved from all 7 public oncology centers in Hong Kong and reviewed. The primary endpoint was progression-free survival (PFS) in first (1L), second (2L), and third or fourth lines (3L or 4L) of CRPC treatment. Secondary endpoints included overall survival (OS), prostate-specific antigen (PSA) response, and tolerance. RESULTS Among a total of 117 patients (median age of 73 years [range, 52-90 years]), 34 (29.1%), 57 (48.7%), and 26 (19.3%) patients had enzalutamide as their 1L (chemo-naive), 2L (post-docetaxel or -abiraterone), and 3L or above treatment options. The overall PSA response rates were 43.6%, and were 73.5%, 35.1%, and 19.2% for 1L, 2L, and 3L or 4L treatment, respectively. PFS and OS were significantly associated with the line of treatment in the univariate survival analysis (1L/2L/3L and 4L; PFS, 7.1/3.9/2.2 months; OS, not reached/15.8/7.4 months; both P = .0002) but not in the multivariate analysis. The observed incidence of any fatigue (grade 1 or 2, 54.7%; grade 3 or 4, 9.4%) was much higher than reported in the AFFIRM (A Study Evaluating the Efficacy and Safety of the Investigational Drug MDV3100 [ClinicalTrials.gov Identifier: NCT00974311]) (any grade, 34%) and PREVAIL (A Multinational Phase 3, Randomized, Double-blind, Placebo-controlled Efficacy And Safety Study Of Oral Mdv3100 In Chemotherapy-naïve Patients With Progressive Metastatic Prostate Cancer Who Have Failed Androgen Deprivation Therapy [ClinicalTrials.gov Identifier: NCT00974311]) (any grade, 36%) trials; as well, grade ≥ 2 fatigue was significantly associated with 3L or 4L treatment (P = .01 in both univariate and multivariate analyses). CONCLUSION In the real-life setting, there was a higher incidence of enzalutamide-related fatigue than reported in the trials. Earlier lines of enzalutamide treatment were associated with longer PFS and OS, more frequent PSA response, and less fatigue.
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Abstract
PURPOSE OF REVIEW To update treatment options and considerations for castration-resistant prostate cancer with specific attention to sequencing of agents based on available evidence and treatment rationale. RECENT FINDINGS The newest research developments over the last several years include multicenter studies that address the sequencing of therapies to improve the treatment of metastatic castration-resistant prostate cancer. Chemotherapy agents, as well as androgen receptor antagonists, are evolving, and there are new tests available to define which patients are more likely to benefit. In addition, there have been some additional trials looking into the safety and efficacy of combination treatment and new therapies. There are multiple factors that should be considered to determine the sequence and/or combinations of therapies for metastatic castration-resistant prostate cancer that can improve quality of life and survival. Promising novel agents in combination with personalized medicine will likely continue to improve treatment of these patients.
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de Bono JS, Chowdhury S, Feyerabend S, Elliott T, Grande E, Melhem-Bertrandt A, Baron B, Hirmand M, Werbrouck P, Fizazi K. Antitumour Activity and Safety of Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer Previously Treated with Abiraterone Acetate Plus Prednisone for ≥24 weeks in Europe. Eur Urol 2018; 74:37-45. [DOI: 10.1016/j.eururo.2017.07.035] [Citation(s) in RCA: 82] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Accepted: 07/26/2017] [Indexed: 10/19/2022]
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Miyake H, Sugiyama T, Aki R, Matsushita Y, Tamura K, Motoyama D, Ito T, Otsuka A. Comparison of Alternative Androgen Receptor-axis-targeted Agent (ARATA) and Docetaxel as Second-line Therapy for Patients With Metastatic Castration-resistant Prostate Cancer With Progression After Initial ARATA in Real-world Clinical Practice in Japan. Clin Genitourin Cancer 2018; 16:219-225. [DOI: 10.1016/j.clgc.2017.11.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Revised: 11/14/2017] [Accepted: 11/27/2017] [Indexed: 10/18/2022]
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Abstract
OPINION STATEMENT Prostate cancer is the most common non-cutaneous cancer diagnosed in men and the second leading cause of male cancer deaths in the USA. While most cases are diagnosed in early stages, some will present as or progress to metastatic disease and eventually castration-resistant prostate cancer (mCRPC) which has a mortality rate exceeding 50 %. There are currently six approved systemic life-prolonging therapies for use in mCRPC, yet little data to guide sequencing. Clinical factors, including the presence or absence of symptoms and the presence or absence of visceral metastases, should help determine the best therapeutic choice at each treatment node. Those with asymptomatic bone-only disease could be considered for sipuleucel-T, abiraterone, enzalutamide, or docetaxel in the first-line setting. For symptomatic disease, docetaxel could be used or radium-223 if disease is only present in the bone. In the second-line setting, sipuleucel-T or radium-223 can be used in the appropriate clinical setting. Taxane chemotherapy could be used if a novel androgen-directed therapy was used in the first-line setting. Cabazitaxel, if docetaxel was previously used, should be considered. There is scarce data on best treatment options in the third-line setting. In general, we recommend alternating between androgen-targeting agents and taxane chemotherapy. Finally, consideration should be given to testing for the androgen receptor splice variant AR-V7, which may be a relevant treatment-specific biomarker to aid in the selection of androgen-targeting therapy versus chemotherapy at each treatment juncture. Mutation testing for DNA damage repair defects can also be considered, as such patients may benefit from investigational poly ADP ribose polymerase (PARP) inhibitors or platinum-based chemotherapies. Several ongoing studies have been designed to answer some of these sequencing questions, including the biomarker questions, and will hopefully continue to inform us about rational therapy selection in mCRPC.
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Miyake H, Sugiyama T, Aki R, Matsushita Y, Tamura K, Motoyama D, Ito T, Otsuka A. No significant impact of prior treatment profile with docetaxel on the efficacy of cabazitaxel in Japanese patients with metastatic castration-resistant prostate cancer. Med Oncol 2017; 34:141. [PMID: 28718092 DOI: 10.1007/s12032-017-1005-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Accepted: 07/14/2017] [Indexed: 11/27/2022]
Abstract
The objective of this study was to retrospectively analyze the oncological outcomes of Japanese patients with metastatic castration-resistant prostate cancer (mCRPC) who received cabazitaxel. This study included a total of 63 consecutive Japanese mCRPC patients treated with cabazitaxel following the failure of docetaxel, and assessed the prognostic significance of cabazitaxel therapy in these patients focusing on the association of efficacies between two taxane agents. After treatment with cabazitaxel (median 5 cycles), prostate-specific antigen (PSA) decline was observed in 39 patients (61.9%), including 13 (27.0%) achieving the response defined by PSA decline ≥50%. The median progression-free survival (PFS) and overall survival (OS) periods after the introduction of cabazitaxel were 4.1 and 14.8 months, respectively. The response rate to cabazitaxel was not significantly different between responders and non-responders to prior docetaxel, and there was no significant correlation between the PFSs with docetaxel and cabazitaxel. Furthermore, univariate analyses of several parameters identified the performance status (PS) and clinical symptoms, but not the cycles of docetaxel therapy, total amount of administered docetaxel or objective response to docetaxel therapy, as significant predictors of OS on cabazitaxel therapy, of which only PS was independently associated with OS on multivariate analysis. These findings suggest that oncological outcomes in Japanese mCRPC patients receiving cabazitaxel are generally satisfactory, irrespective of the profiles related to prior treatment with docetaxel, and that it might be preferable to introduce cabazitaxel to mCRPC patients with a good PS to maximize the prognostic benefit of this agent.
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Affiliation(s)
- Hideaki Miyake
- Department of Urology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, 431-3192, Japan.
| | - Takayuki Sugiyama
- Department of Urology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, 431-3192, Japan
| | - Ryota Aki
- Department of Urology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, 431-3192, Japan
| | - Yuto Matsushita
- Department of Urology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, 431-3192, Japan
| | - Keita Tamura
- Department of Urology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, 431-3192, Japan
| | - Daisuke Motoyama
- Department of Urology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, 431-3192, Japan
| | - Toshiki Ito
- Department of Urology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, 431-3192, Japan
| | - Atsushi Otsuka
- Department of Urology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, 431-3192, Japan
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Oh WK, Miao R, Vekeman F, Sung J, Cheng WY, Gauthier-Loiselle M, Dhawan R, Duh MS. Real-world Characteristics and Outcomes of Patients With Metastatic Castration-resistant Prostate Cancer Receiving Chemotherapy Versus Androgen Receptor-targeted Therapy After Failure of First-line Androgen Receptor-targeted Therapy in the Community Setting. Clin Genitourin Cancer 2017; 16:S1558-7673(17)30170-2. [PMID: 28729067 DOI: 10.1016/j.clgc.2017.06.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Revised: 06/09/2017] [Accepted: 06/13/2017] [Indexed: 11/19/2022]
Abstract
BACKGROUND In metastatic castration-resistant prostate cancer (mCRPC), optimal treatment sequences are unknown. We assessed second-line taxane (TT) versus androgen receptor-targeted therapy (ART), after initial ART failure, in United States oncology community practices. PATIENTS AND METHODS Using electronic medical records, patients with mCRPC receiving first-line ART and second-line therapy (TT, ART) were identified. Response and overall survival (OS) were evaluated from second-line therapy initiation. Multivariate analyses were adjusted for year, age, metastases, opioid use, prostate-specific antigen (PSA), hemoglobin, alkaline phosphatase, and albumin levels. RESULTS Of 546 patients receiving first-line ART, 206 and 340 received second-line TT and ART. Compared with patients receiving second-line ART, patients receiving TT were younger (median, 74 vs. 79 years), more had intermediate-high Halabi risk scores (59% vs. 35%), had higher opioid use (42% vs. 22%), median PSA (116 vs. 48 ng/mL), alkaline phosphatase (112 vs. 87 U/L), and lactate dehydrogenase (254 vs. 201 U/L), and had lower hemoglobin (11.2 vs. 12.3 g/dL) and albumin levels (3.8 vs. 4.0 g/dL); all P < .001. Response rates were higher with second-line TT versus ART (clinical response, 44.2% vs. 24.7%; P = .006; PSA response, 44.5% vs. 28.7%; P = .004). OS did not differ between cohorts (hazard ratio [HR], 0.90; P = .511). Among patients with a poor prognosis (hemoglobin < 11 g/d; albumin < lower limit of normal), those receiving second-line TT versus ART showed improved OS (HR, 0.52; P = .004 and HR, 0.36; P = .003, respectively). CONCLUSIONS Despite more severe disease profiles, patients with mCRPC receiving second-line TT versus ART achieved higher response rates after initial ART. Poor prognosis patients had improved OS with second-line TT versus ART.
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Affiliation(s)
- William K Oh
- Division of Hematology/Medical Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
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Conteduca V, Crabb SJ, Scarpi E, Hanna C, Maines F, Joyce H, Fabbri P, Derosa L, Massari F, Lolli C, Zarif S, Jones RJ, Caffo O, Elliott T, De Giorgi U. Association Between Early PSA Increase and Clinical Outcome in Patients Treated with Enzalutamide for Metastatic Castration Resistant Prostate Cancer. Mol Diagn Ther 2017; 20:255-63. [PMID: 27020582 DOI: 10.1007/s40291-016-0196-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
OBJECTIVE Prostate-specific antigen (PSA) decline by 50 % from the baseline to 12 weeks (PSA50w12) is currently used to predict response to treatment and clinical outcome of patients with metastatic castration-resistant prostate cancer (mCRPC). We evaluated the association between PSA changes at 4 weeks and clinical outcome. PATIENTS AND METHODS Eligible patients had PSA levels assessed at baseline, and monthly during enzalutamide treatment. Early PSA increase was defined as an increased PSA level at 4 weeks ≥20 % (PSA + 20w4) from baseline. Early PSA decline was defined as a PSA response at 4 weeks ≥30 % (PSA30w4) and ≥50 % (PSA50w4) from baseline. Progression-free survival (PFS), overall survival (OS) and their 95 % confidence intervals (CI) were evaluated by the Kaplan-Meier method and compared with the log-rank test. The impact of early PSA increase and decline on PFS and OS was evaluated by Cox regression analyses. RESULTS We assessed 193 patients with median age of 73 years (range 43-91 years). The median follow-up was 11.7 months (range 0.5-27.4 months). PSA + 20w4 predicted both PFS and OS [HR 6.50 (95 % CI 2.63-16.07; p < 0.0001) and HR 10.54 (95 % CI 4.02-27.64; p < 0.0001), respectively], whereas PSA30w4 and PSA50w4 predicted only PFS [HR 0.37 (95 % CI 0.21-0.67; p = 0.0009) and HR 0.34 (95 % CI 0.19-0.60; p = 0.0003), respectively]. CONCLUSIONS An early PSA increase, defined as a PSA level at 4 weeks ≥20 % (PSA + 20w4), could be useful to quickly identify patients unlikely to benefit from enzalutamide. Larger studies are needed to confirm PSA + 20W4 as an early biomarker of primary resistance to enzalutamide.
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Affiliation(s)
- Vincenza Conteduca
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.) IRCCS, Via Piero Maroncelli 40, 47014, Meldola, FC, Italy
| | - Simon J Crabb
- Cancer Sciences Unit, University of Southampton, Southampton, UK
| | - Emanuela Scarpi
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.) IRCCS, Via Piero Maroncelli 40, 47014, Meldola, FC, Italy
| | | | - Francesca Maines
- Medical Oncology Department, Santa Chiara Hospital, Trento, Italy
| | | | - Paolo Fabbri
- Oncology Unit, Cervesi Hospital, Cattolica, Italy
| | - Lisa Derosa
- Medical Oncology Department, Santa Chiara Hospital, Pisa, Italy
| | - Francesco Massari
- Medical Oncology, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Cristian Lolli
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.) IRCCS, Via Piero Maroncelli 40, 47014, Meldola, FC, Italy
| | - Sunnya Zarif
- Cancer Sciences Unit, University of Southampton, Southampton, UK
| | - Robert J Jones
- Beatson West of Scotland Cancer Centre, Glasgow, UK
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Orazio Caffo
- Medical Oncology Department, Santa Chiara Hospital, Trento, Italy
| | | | - Ugo De Giorgi
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.) IRCCS, Via Piero Maroncelli 40, 47014, Meldola, FC, Italy.
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[Advanced Prostate Cancer Consensus Conference (APCCC) 2015 in St. Gallen : Critical review of the recommendations on diagnosis and therapy of metastatic prostate cancer by a German expert panel]. Urologe A 2017; 55:772-82. [PMID: 26820660 DOI: 10.1007/s00120-016-0030-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
In March 2015, the first Advanced Prostate Cancer Consensus Conference (APCC) took place in St. Gallen. 41 experts from 17 countries reviewed important areas of controversy in advanced hormone-naive and castration-resistant prostate cancer and gave therapy recommendations. These results have been recently published in "Annals of Oncology". While most of the recommendations from St. Gallen are comprehensible, some of them need to be further discussed. Therefore, we as a German expert panel will critically debate the St. Gallen recommendations. For metastatic hormone-naive prostate cancer, continuous androgen deprivation remains the standard. There is no evidence for superiority of primary maximal androgen deprivation. Patients suitable for chemotherapy, especially in the presence of high tumour burden, should receive androgen deprivation plus taxanes upfront. In metastatic castration resistant prostate cancer, novel hormonal agents like abiraterone or enzalutamid should be the treatment of choice in the majority of patients. Taxanes should be used first-line in patients with unfavourable prognostic markers. Radium-223 is an option in symptomatic patients with bone metastases. There is first evidence that second-line hormonal treatment after first-line failure of a novel endocrine agent has a high failure rate. Cabazitaxel should be part of the treatment sequence in patients with a good performance status. Baseline staging for castration-resistant prostate cancer should include CT-abdomen/-chest and bone scan. Radiographic monitoring should be performed 2 to 3 times a year. Determination of PSA and ALP is to take place every 2 to 4 months.
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Ceci F, Castellucci P, Mapelli P, Incerti E, Picchio M, Fanti S. Evaluation of Prostate Cancer with 11C-Choline PET/CT for Treatment Planning, Response Assessment, and Prognosis. J Nucl Med 2017; 57:49S-54S. [PMID: 27694172 DOI: 10.2967/jnumed.115.170126] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2016] [Accepted: 07/05/2016] [Indexed: 01/29/2023] Open
Abstract
The aim of this review is to report on the value of 11C-choline PET imaging as a diagnostic procedure for metastasis-directed therapies. Furthermore, the role of 11C-choline PET/CT as a diagnostic tool for monitoring castration-resistant prostate cancer patients treated with systematic therapy is assessed. Finally, the role of 11C-choline PET/CT in the prediction of survival in both castration-resistant prostate cancer patients and hormone-naïve patients is investigated.
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Affiliation(s)
- Francesco Ceci
- Service of Nuclear Medicine, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy; and
| | - Paolo Castellucci
- Service of Nuclear Medicine, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy; and
| | - Paola Mapelli
- Service of Nuclear Medicine, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Elena Incerti
- Service of Nuclear Medicine, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Maria Picchio
- Service of Nuclear Medicine, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Stefano Fanti
- Service of Nuclear Medicine, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy; and
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Terada N, Maughan BL, Akamatsu S, Kobayashi T, Yamasaki T, Inoue T, Kamba T, Ogawa O, Antonarakis ES. Exploring the optimal sequence of abiraterone and enzalutamide in patients with chemotherapy-naïve castration-resistant prostate cancer: The Kyoto-Baltimore collaboration. Int J Urol 2017; 24:441-448. [PMID: 28455853 DOI: 10.1111/iju.13346] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Accepted: 03/06/2017] [Indexed: 01/16/2023]
Abstract
OBJECTIVES To evaluate and compare the efficacy of sequential treatment with abiraterone followed by enzalutamide or vice versa for castration-resistant prostate cancer. METHODS We retrospectively evaluated data on 198 consecutive chemotherapy-naïve patients who had received both abiraterone and enzalutamide for castration-resistant prostate cancer at Kyoto University Hospital (including satellite hospitals) and at Johns Hopkins Cancer Center. Prostate-specific antigen progression-free survival and overall survival in patients treated with sequential abiraterone-to-enzalutamide versus enzalutamide-to-abiraterone without intervening therapies were compared. RESULTS Overall, 113 patients were treated with the abiraterone-to-enzalutamide sequence and 85 with the enzalutamide-to-abiraterone sequence. Median prostate-specific antigen progression-free survival was not significantly different between abiraterone and enzalutamide in the first-line setting (hazard ratio 0.88, 95% confidence interval 0.66-1.19, P = 0.412), but there was an advantage favoring enzalutamide compared with abiraterone in the second-line setting (hazard ratio 0.67, 95% confidence interval 0.49-0.91, P = 0.009). Furthermore, the combined prostate-specific antigen progression-free survival was significantly longer in the abiraterone-to-enzalutamide sequence than in the enzalutamide-to-abiraterone sequence (hazard ratio 0.56, 95% confidence interval 0.41-0.76, P < 0.001). The difference was significant even in multivariate analyses (hazard ratio 0.65, 95% confidence interval 0.42-0.99, P = 0.044). There was no statistical difference in overall survival between the two sequences in univariate (hazard ratio 0.88, 95% confidence interval 0.53-1.43, P = 0.599) and multivariate analyses (hazard ratio 0.81, 95% confidence interval 0.49-1.35, P = 0.427). CONCLUSIONS The abiraterone-to-enzalutamide sequence might have more favorable efficacy in terms of combined prostate-specific antigen progression-free survival than the enzalutamide-to-abiraterone sequence, although no differences in overall survival were observed. This could possibly be attributable to longer prostate-specific antigen progression-free survival with second-line enzalutamide compared with abiraterone.
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Affiliation(s)
- Naoki Terada
- Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Benjamin L Maughan
- Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA
| | - Shusuke Akamatsu
- Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Takashi Kobayashi
- Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Toshinari Yamasaki
- Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Takahiro Inoue
- Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Tomomi Kamba
- Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Osamu Ogawa
- Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan
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Early use of chemotherapy in metastatic prostate cancer. Cancer Treat Rev 2017; 55:218-224. [PMID: 27720577 PMCID: PMC9774055 DOI: 10.1016/j.ctrv.2016.09.017] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Revised: 09/16/2016] [Accepted: 09/23/2016] [Indexed: 12/24/2022]
Abstract
Since 2010, five new antineoplastic therapies have been FDA approved for the treatment of metastatic prostate cancer. With additional treatment options, questions arose about the optimal sequence of these agents. Until recently, chemotherapy has been deferred until later in the disease course in favor of next-generation androgen deprivation therapy. Prior to the development of abiraterone acetate and enzalutamide, clinical trials were opened investigating the combination of chemotherapy with androgen deprivation therapy in patients with metastatic hormone-sensitive disease. With the development of new oral therapies used to treat castration-resistant disease, these trials were largely forgotten or felt to be obsolete. Recently, two trials have been reported showing an overall survival benefit of the early use of chemotherapy in patients with hormone-naive prostate cancer, changing the treatment paradigm for metastatic disease. Here we review the history of chemotherapy in treating prostate cancer and the emerging evidence favoring its use as first-line therapy against metastatic hormone-sensitive disease.
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Poorthuis MHF, Vernooij RWM, van Moorselaar RJA, de Reijke TM. First-line non-cytotoxic therapy in chemotherapy-naive patients with metastatic castration-resistant prostate cancer: a systematic review of 10 randomised clinical trials. BJU Int 2017; 119:831-845. [PMID: 28063195 DOI: 10.1111/bju.13764] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The aim of this study is to systematically evaluate all available treatment options in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (mCRPC). We systematically searched PubMed, EMBASE, and the Cochrane libraries up to 1 March 2016 for peer-reviewed publications on randomised clinical trials (RCTs). RCTs were included if progression-free survival (PFS), overall survival (OS), quality of life (QoL), or adverse events (AEs) were quantitatively evaluated. We assessed the risk of bias with the Cochrane Collaboration's tool and graded the evidence with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group's approach. We included 25 articles, reporting on 10 unique RCTs describing seven different comparisons. In one RCT, a prolonged OS and PFS (high quality) were found with abiraterone and prednisone compared to placebo plus prednisone. In one RCT, a prolonged OS and PFS (high quality) were found with enzalutamide compared to placebo. In two RCTs, a prolonged OS (high and moderate quality) was found with 223 radium compared to placebo, but its effect on PFS is unknown. In three RCTs, a prolonged OS (moderate quality) was found with sipuleucel-T compared to placebo, but no prolonged PFS (low quality). In one RCT a prolonged PFS (high quality) was found with orteronel compared to placebo, but no prolonged OS (moderate quality). In one RCT, a prolonged OS (moderate quality) was found with bicalutamide compared to placebo, but its effect on PFS is unknown. In one RCT, a prolonged PFS (high quality) was found with enzalutamide compared to bicalutamide, but its effect on OS is unknown. The best evidence was found for abiraterone and enzalutamide for effective prolongation of OS and PFS to treat chemotherapy-naive patients with mCRPC. However, taking both QoL and AEs into consideration, other treatment modalities could be considered for individual patients.
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Affiliation(s)
- Michiel H F Poorthuis
- Department of Research, Netherlands Comprehensive Cancer Organisation (IKNL), Utrecht, The Netherlands
| | - Robin W M Vernooij
- Department of Research, Netherlands Comprehensive Cancer Organisation (IKNL), Utrecht, The Netherlands
| | | | - Theo M de Reijke
- Department of Urology, Academic Medical Center, Amsterdam, The Netherlands
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AR-Signaling in Human Malignancies: Prostate Cancer and Beyond. Cancers (Basel) 2017; 9:cancers9010007. [PMID: 28085048 PMCID: PMC5295778 DOI: 10.3390/cancers9010007] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Revised: 01/04/2017] [Accepted: 01/05/2017] [Indexed: 12/11/2022] Open
Abstract
In the 1940s Charles Huggins reported remarkable palliative benefits following surgical castration in men with advanced prostate cancer, and since then the androgen receptor (AR) has remained the main therapeutic target in this disease. Over the past couple of decades, our understanding of AR-signaling biology has dramatically improved, and it has become apparent that the AR can modulate a number of other well-described oncogenic signaling pathways. Not surprisingly, mounting preclinical and epidemiologic data now supports a role for AR-signaling in promoting the growth and progression of several cancers other than prostate, and early phase clinical trials have documented preliminary signs of efficacy when AR-signaling inhibitors are used in several of these malignancies. In this article, we provide an overview of the evidence supporting the use of AR-directed therapies in prostate as well as other cancers, with an emphasis on the rationale for targeting AR-signaling across tumor types.
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Maughan BL, Luber B, Nadal R, Antonarakis ES. Comparing Sequencing of Abiraterone and Enzalutamide in Men With Metastatic Castration-Resistant Prostate Cancer: A Retrospective Study. Prostate 2017; 77:33-40. [PMID: 27527643 DOI: 10.1002/pros.23246] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Accepted: 07/29/2016] [Indexed: 11/11/2022]
Abstract
BACKGROUND There are no validated clinical decision tools to aid optimal treatment selection in men with metastatic castration-resistant prostate cancer (mCRPC). Frequently, abiraterone and enzalutamide are used prior to chemotherapy in mCRPC, given the more favorable safety profiles. However, there is no published data on clinical outcomes regarding best sequencing of these two agents. METHODS A retrospective analysis of consecutive mCRPC patients treated with enzalutamide and abiraterone at Johns Hopkins was conducted. Patients were treated with sequential enzalutamide and abiraterone, in either order. The combined progression-free survival (PFS: PFS1 + PFS2) of abiraterone-to-enzalutamide was compared to the reverse sequence, where PFS1 and PFS2 represented clinical/radiographic progression-free survival on the first and second agents, respectively. Overall survival (OS) from the start of the first therapy to death and PSA response rates (defined as ≥50% PSA declines at any time) were also compared between groups. Outcomes were adjusted using propensity score-weighted multivariable Cox analyses. RESULTS Eighty-one patients who satisfied our entry criteria were identified: 65 in the abiraterone-to-enzalutamide group and 16 in the enzalutamide-to-abiraterone group. There were no significant baseline differences between groups. Multivariable analysis suggested a difference between groups favoring the abiraterone-to-enzalutamide sequence with respect to combined PFS (HR 0.37, 95%CI 0.22-0.64, P < 0.001). There was no statistical difference in OS between the groups after multivariable adjustment (HR 0.57, 95%CI 0.29-1.11, P = 0.098), although OS was numerically superior in the abiraterone-to-enzalutamide group. CONCLUSIONS We observed differences suggesting improved outcomes favoring the abiraterone-to-enzalutamide sequence in men with mCRPC, with statistical confirmation in terms of PFS but not OS. Prospective studies are required to verify these hypothesis-generating findings. Further evaluation of biomarkers to inform optimal treatment sequencing in men with mCRPC is urgently needed. Prostate 77:33-40, 2017. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Benjamin L Maughan
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland
| | - Brandon Luber
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland
| | - Rosa Nadal
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland
| | - Emmanuel S Antonarakis
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland
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Comparative Assessment of Efficacies Between 2 Alternative Therapeutic Sequences With Novel Androgen Receptor-Axis-Targeted Agents in Patients With Chemotherapy-Naïve Metastatic Castration-Resistant Prostate Cancer. Clin Genitourin Cancer 2016; 15:e591-e597. [PMID: 28063845 DOI: 10.1016/j.clgc.2016.12.015] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2016] [Revised: 12/04/2016] [Accepted: 12/10/2016] [Indexed: 12/20/2022]
Abstract
BACKGROUND The objective of this study was to compare the efficacies of sequential therapies with novel androgen receptor-axis-targeted (ARAT) agents in patients with docetaxel-naïve metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS This study included 108 consecutive patients with mCRPC who sequentially received abiraterone acetate (AA) and enzalutamide (Enz), in either order, without prior treatment with docetaxel. The combined prostate-specific antigen (PSA) progression-free survival (PFS) was defined as the sum of PFS1 and PFS2, representing PSA PFSs on the first and second ARAT agents, respectively. RESULTS Of these patients, 49 and 59 received ARAT therapy with the AA-to-Enz sequence (AA-to-Enz group) and with the reverse sequence (Enz-to-AA group), respectively. No significant differences in the baseline characteristics were noted between the 2 groups. In the overall patient population, the PSA response rate to the second-line ARAT agent (21.3%) was significantly lower than that of the first-line ARAT agent (58.3%). The combined PSA PFS in the AA-to-Enz group (median, 18.4 months) was significantly superior to that of the Enz-to-AA group (median, 12.8 months). Furthermore, multivariate analysis identified the treatment sequence (ie, AA-to-Enz vs. Enz-to-AA group) in addition to performance status as an independent predictor of combined PSA PFS in these patients. However, there was no significant difference in overall survival (OS) between the 2 groups. CONCLUSIONS Although cross-resistance between ARAT agents is a common phenomenon in docetaxel-naïve patients with mCRPC, different efficacies were observed favoring the AA-to-Enz rather than Enz-to-AA sequence in this series with respect to combined PSA PFS but not OS.
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Lam HM, McMullin R, Nguyen HM, Coleman I, Gormley M, Gulati R, Brown LG, Holt SK, Li W, Ricci DS, Verstraeten K, Thomas S, Mostaghel EA, Nelson PS, Vessella RL, Corey E. Characterization of an Abiraterone Ultraresponsive Phenotype in Castration-Resistant Prostate Cancer Patient-Derived Xenografts. Clin Cancer Res 2016; 23:2301-2312. [PMID: 27993966 DOI: 10.1158/1078-0432.ccr-16-2054] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Revised: 11/09/2016] [Accepted: 12/08/2016] [Indexed: 01/02/2023]
Abstract
Purpose: To identify the molecular signature associated with abiraterone acetate (AA) response and mechanisms underlying AA resistance in castration-resistant prostate cancer patient-derived xenografts (PDXs).Experimental Design: SCID mice bearing LuCaP 136CR, 77CR, 96CR, and 35CR PDXs were treated with AA. Tumor volume and prostate-specific antigen were monitored, and tumors were harvested 7 days after treatment or at end of study for gene expression and immunohistochemical studies.Results: Three phenotypic groups were observed based on AA response. An ultraresponsive phenotype was identified in LuCaP 136CR with significant inhibition of tumor progression and increased survival, intermediate responders LuCaP 77CR and LuCaP 96CR with a modest tumor inhibition and survival benefit, and LuCaP 35CR with minimal tumor inhibition and no survival benefit upon AA treatment. We identified a molecular signature of secreted proteins associated with the AA ultraresponsive phenotype. Upon resistance, AA ultraresponder LuCaP 136CR displayed reduced androgen receptor (AR) signaling and sustainably low nuclear glucocorticoid receptor (nGR) localization, accompanied by steroid metabolism alteration and epithelial-mesenchymal transition phenotype enrichment with increased expression of NF-κB-regulated genes; intermediate and minimal responders maintained sustained AR signaling and increased tumoral nGR localization.Conclusions: We identified a molecular signature of secreted proteins associated with AA ultraresponsiveness and sustained AR/GR signaling upon AA resistance in intermediate or minimal responders. These data will inform development of noninvasive biomarkers predicting AA response and suggest that further inhibition along the AR/GR signaling axis may be effective only in AA-resistant patients who are intermediate or minimal responders. These findings require verification in prospective clinical trials. Clin Cancer Res; 23(9); 2301-12. ©2016 AACR.
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Affiliation(s)
- Hung-Ming Lam
- Department of Urology, University of Washington, Seattle, Washington.,State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), China
| | | | - Holly M Nguyen
- Department of Urology, University of Washington, Seattle, Washington
| | - Ilsa Coleman
- Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Michael Gormley
- Janssen Research and Development, Spring House, Pennsylvania
| | - Roman Gulati
- Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Lisha G Brown
- Department of Urology, University of Washington, Seattle, Washington
| | - Sarah K Holt
- Department of Urology, University of Washington, Seattle, Washington
| | - Weimin Li
- Janssen Research and Development, Spring House, Pennsylvania
| | | | | | - Shibu Thomas
- Janssen Research and Development, Spring House, Pennsylvania
| | - Elahe A Mostaghel
- Fred Hutchinson Cancer Research Center, Seattle, Washington.,Department of Medicine, University of Washington, Seattle, Washington
| | - Peter S Nelson
- Fred Hutchinson Cancer Research Center, Seattle, Washington.,Department of Medicine, University of Washington, Seattle, Washington
| | - Robert L Vessella
- Department of Urology, University of Washington, Seattle, Washington.,Department of Veterans Affairs Medical Center, Seattle, Washington
| | - Eva Corey
- Department of Urology, University of Washington, Seattle, Washington.
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Antonarakis ES, Chandhasin C, Osbourne E, Luo J, Sadar MD, Perabo F. Targeting the N-Terminal Domain of the Androgen Receptor: A New Approach for the Treatment of Advanced Prostate Cancer. Oncologist 2016; 21:1427-1435. [PMID: 27628492 PMCID: PMC5153341 DOI: 10.1634/theoncologist.2016-0161] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2016] [Accepted: 07/08/2016] [Indexed: 12/19/2022] Open
Abstract
: Despite the recent approval and widespread use of abiraterone acetate and enzalutamide for the treatment of castration-resistant prostate cancer (CRPC), this disease still poses significant management challenges because of various tumor escape mechanisms, including those that allow androgen receptor (AR) signaling to remain active. These AR-related resistance mechanisms include AR gene amplification or overexpression, constitutively active ligand-independent AR splice variants, and gain-of-function mutations involving the AR ligand-binding domain (LBD), among others. Therefore, the development of AR-targeted therapies that function independently of the LBD represents an unmet medical need and has the potential to overcome many of these resistance mechanisms. This article discusses N-terminal domain (NTD) inhibition as a novel concept in the field of AR-directed therapies for prostate cancer. AR NTD-targeting agents have the potential to overcome shortcomings of current hormonal therapies by inhibiting all forms of AR-mediated transcriptional activity, and as a result, may affect a broader AR population including mutational and splice variant ARs. Indeed, the first clinical trial of an AR NTD inhibitor is now underway. IMPLICATIONS FOR PRACTICE Because of emerging resistance mechanisms that involve the ligand-binding domain of the androgen receptor (AR), there is currently no effective treatment addressing tumor escape mechanisms related to current AR-targeted therapies. Many patients still demonstrate limited clinical response to current hormonal agents, and castration-resistant prostate cancer remains a lethal disease. Intense research efforts are under way to develop therapies to target resistance mechanisms, including those directed at other parts of the AR molecule. A novel small-molecule agent, EPI-506, represents a new pharmaceutical class, AR N-terminal domain inhibitors, and shows preclinical promise to overcome many known resistance mechanisms related to novel hormonal therapies.
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Affiliation(s)
- Emmanuel S Antonarakis
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA
- Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University, Baltimore, Maryland, USA
| | | | | | - Jun Luo
- Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University, Baltimore, Maryland, USA
| | | | - Frank Perabo
- ESSA Pharmaceuticals Corporation, Houston, Texas, USA
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Lohiya V, Aragon-Ching JB, Sonpavde G. Role of Chemotherapy and Mechanisms of Resistance to Chemotherapy in Metastatic Castration-Resistant Prostate Cancer. Clin Med Insights Oncol 2016; 10:57-66. [PMID: 27773999 PMCID: PMC5065075 DOI: 10.4137/cmo.s34535] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Revised: 08/30/2016] [Accepted: 09/03/2016] [Indexed: 12/13/2022] Open
Abstract
Chemotherapy using the taxanes, docetaxel and cabazitaxel, remains an important therapeutic option in metastatic castration-resistant prostate cancer (CRPC). However, despite the survival benefits afforded by these agents, the survival increments are modest and resistance occurs universally. Efforts to overcome resistance to docetaxel by combining with biologic agents have heretofore been unsuccessful. Indeed, resistance to these taxanes is also associated with cross-resistance to the antiandrogen drugs, abiraterone and enzalutamide. Here, we discuss the various mechanisms of resistance to chemotherapy in metastatic CRPC and the potential role of emerging regimens and agents in varying clinical phases of development.
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Affiliation(s)
- Vipin Lohiya
- Division of Hematology-Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | | | - Guru Sonpavde
- Division of Hematology-Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
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