Three-weekly docetaxel plus prednisone is the standard first-line cytotoxic treatment for patients with metastatic castrate-resistant prostate cancer (mCRPC). Today, several new treatment options are available for patients with tumor progression after first-line docetaxel: Abiraterone, enzalutamide, cabazitaxel, sipuleucel-T immunotherapy, and the radionuclide radium-223. However, despite the evolving scenario in CRPC treatment, the optimal sequencing of the innovative therapies remains unclear. The reintroduction of docetaxel at the occurrence of disease progression after a drug holiday (docetaxel rechallenge) was often proposed, and this chemotherapeutic agent showed to maintain antitumor activity in mCRPC patients. Docetaxel rechallenge may still constitute a valid treatment option mainly for patients with favorable response to first-line docetaxel, at least > 3 mo progression-free interval, age less than 75 years, good performance status, and acceptable docetaxel toxicity. The risk of cumulative toxicity must be evaluated, since sensory neuropathy, nail disorders and fatigue might occur on docetaxel rechallenge.

Changes in serum tumor biomarkers may indicate treatment efficacy. Traditional tumor markers may soon be replaced by novel serum biomarkers, such as circulating tumor cells (CTCs) or circulating tumor nucleic acids. Given their promising predictive values, studies of their kinetics are warranted. Many methodologies meant to assess kinetics of traditional marker kinetics during anticancer treatment have been reported. Here, we review the methodologies, the advantages and the limitations of the analytical approaches reported in the literature. Strategies based on a single time point were first used (baseline value, normalization, nadir, threshold at a time t), followed by approaches based on two or more time points [half-life (HL), percentage decrease, time-to-events…]. Heterogeneities in methodologies and lack of consideration of inter- and intra-individual variability may account for the inconsistencies and the poor utility in routine. More recently, strategies based on a population kinetics approach and mathematical modeling have been reported. The identification of equations describing individual kinetic profiles of biomarkers may be an alternative strategy despite its complexity and higher number of necessary measurements. Validation studies are required. Efforts should be made to standardize biomarker kinetic analysis methodologies to ensure the optimized development of novel serum biomarkers and avoid the pitfalls of traditional markers.

Prostate cancer (PCa) stem/progenitor cells are known to have higher chemoresistance than non-stem/progenitor cells, but the underlying molecular mechanism remains unclear. We found the expression of testicular nuclear receptor 4 (TR4) is significantly higher in PCa CD133(+) stem/progenitor cells compared with CD133(-) non-stem/progenitor cells. Knockdown of TR4 levels in the established PCa stem/progenitor cells and the CD133(+) population of the C4-2 PCa cell line with lentiviral TR4 siRNA led to increased drug sensitivity to the two commonly used chemotherapeutic drugs, docetaxel and etoposide, judging from significantly reduced IC50 values and increased apoptosis in the TR4 knockdown cells. Mechanism dissection studies found that suppression of TR4 in these stem/progenitor cells led to down-regulation of Oct4 expression, which, in turn, down-regulated the IL-1 receptor antagonist (IL1Ra) expression. Neutralization experiments via adding these molecules into the TR4 knockdown PCa stem/progenitor cells reversed the chemoresistance, suggesting that the TR4-Oct4-IL1Ra axis may play a critical role in the development of chemoresistance in the PCa stem/progenitor cells. Together, these studies suggest that targeting TR4 may alter chemoresistance of PCa stem/progenitor cells, and this finding provides the possibility of targeting TR4 as a new and better approach to overcome the chemoresistance problem in PCa therapeutics.

To describe the feasibility and efficacy of multiple sequential rechallenges and analyze the predictive factors that may aid in selecting patients who are more likely to respond. Several studies have demonstrated the feasibility and activity of a single docetaxel rechallenge in patients with castration-resistant prostate cancer (CRPC), thus providing an additional opportunity for treatment in docetaxel-sensitive CRPC patients in clinical practice.

CRPC patients who completed first-line docetaxel therapy without disease progression have been offered a docetaxel rechallenge, and the responders have undergone further rechallenges until the appearance of docetaxel resistance. We assessed their clinical outcomes and evaluated all the variables potentially capable of predicting the response to rechallenge by means of uni- and multivariate analysis.

Forty-six consecutive patients underwent 92 rechallenges. The overall biochemical response rate (prostate-specific antigen [PSA] reduction >50%) was 66%. Median overall survival was 32 months with a projected 2-year overall survival from the first docetaxel administration of 77.5%. Multivariate analysis showed that the time slope-log PSA, the time from the previous cycle, and the response to the previous cycle were predictive of the response to a rechallenge.

A docetaxel rechallenge may be safely repeated several times in CRPC patients and in selected patients could improve disease control. The predictive factors found in our analysis may help select the most appropriate strategy in the light of the availability of active second-line drugs.

The purpose of this review article is to present the current treatment options for castrate resistant prostate cancer in addition to the recently approved agents and their role in treatment.

The biology of prostate cancer and the data supporting the use of traditional chemotherapeutic options in castrate resistant prostate cancer are reviewed. The newly approved agents, sipuleucel-T, cabazitaxel, and abiraterone, are presented as well. The studies that led to the approval of these three agents are discussed in this article as well as their current and potential roles in the treatment of castrate resistant prostate cancer.

New mechanisms, drugs, and clinically relevant molecular targets show survival advantage and are new options available for patients after traditional chemotherapy. The roles of these new agents have yet to be further clarified in future studies.

The management of castration-resistant prostate cancer (CRPC) presents a clinical challenge because of limitations in efficacy and durability with currently available therapeutics. The epothilones represent a novel class of anticancer therapy that stabilizes microtubules, causing cell death and tumor regression in preclinical models. The structure of the tubulin-binding site for epothilones is distinct from that of the taxanes. Moreover, preclinical studies suggest nonoverlapping mechanisms of resistance between epothilones and taxanes. In early-phase studies in patients with CRPC, treatment with ixabepilone, a semisynthetic analog of epothilone B, induced objective responses and prostate-specific antigen declines in men previously progressing on docetaxel-based regimens. Clinical activity has been observed in nonrandomized trials for patients with CRPC using ixabepilone in the first- and second-line settings as a single agent and in combination with estramustine. Patupilone and sagopilone were also shown to have promising efficacy in phase II clinical trials of patients with CRPC. All three epothilones appear to be well tolerated, with modest rates of neutropenia and peripheral neuropathy. The lack of crossresistance between epothilones and taxanes may allow sequencing of these agents. Evaluating epothilones in phase III comparative trials would provide much-needed insight into their potential place in the management of patients with CRPC.

Although there is no standard treatment after docetaxel failure in patients with castration-resistant prostate cancer (CRPC), second-line chemotherapy is increasingly required. Its mechanism of action and toxicity profile make pemetrexed suitable for testing in this setting.

Patients with docetaxel-resistant CRPC received pemetrexed 500 mg/m(2) every 3 weeks for 6 courses. The usual premedication with vitamin supplementation and dexamethasone prophylaxis was regularly administered. The primary objective was to quantify the biochemical response rate.

The biochemical response rate was 10.5% (95% CI 1.3-33.1), with 2 patients showing a reduction in prostate specific antigen (PSA) of ≥50%. The null hypothesis that the PSA response rate would be less than 20% was therefore accepted, and patient accrual was stopped after the evaluation of the 19th patient. The 1-year overall survival rate was 61.5%, with a median survival of 14 months. A considerable proportion of the patients (36%) were withdrawn from the study because of hematologic and nonhematologic toxicity.

Our experience with pemetrexed in CRPC patients appears discouraging in terms of activity and toxicity. No further studies of this drug should be performed in CRPC patients.

What's known on the subject? and What does the study add? Estramustine phosphate has anti-tumour properties and it improves patient outcomes if combined with other chemotherapy agents such as docetaxel. The efficacy of estramustine phosphate in selected patients and its safety profile, provided used with any low-molecular-weight heparin support its use as a second-line treatment in hormone-resistant prostate cancer.

•  Estramustine phosphate is a nitrogen mustard derivative of estradiol-17β-phosphate and has anti-tumour properties. •  Interest in estramustine has been renewed because of the results of clinical studies showing improved patient outcomes if estramustine is combined with other chemotherapy agents such as docetaxel.

•  Relevant clinical studies using chemotherapy combinations including estramustine are discussed. •  Efficacy and safety outcomes are summarized.

•  Combination therapy with estramustine and docetaxel can increase PSA response rates, improve quality of life and increase median patient survival compared with chemotherapy regimens that do not include estramustine. •  Although the overall tolerability of estramustine is favourable, its use can be associated with an increased risk of thromboembolic events.

•  The identification of suitable patient groups and the effective management of the risk of thromboembolism with the adjunct of low-molecular-weight heparins support the use of estramustine as an effective second-line treatment strategy in hormone-resistant prostate cancer. •  These promising findings warrant further investigation in a randomized clinical trial.

Docetaxel-based therapy is established as the standard first-line chemotherapy in patients with metastatic castration-resistant prostate cancer (mCRPC), based on results from two landmark Phase III studies. However, prognosis remains poor, with a median survival of less than 2 years. There is no standard of care for patients who progress during or after docetaxel treatment, which represents a real unmet medical need. Several small retrospective studies suggest that patients with mCRPC who responded to first-line docetaxel-based therapy are sensitive to re-treatment, but a survival benefit in prospective randomized trials has not been demonstrated. Epithelial-stromal interactions in the tumour microenvironment appear to play a central role in prostate cancer progression and response to therapy. Recent insights into the molecular mechanisms that underpin prostate cancer progression have allowed the identification of potential therapeutic targets. New agents, including angiogenesis inhibitors, hormone therapies, chemotherapies, bone targeting agents, vaccines and immunotherapies are currently undergoing clinical development in advanced prostate cancer using docetaxel as a backbone. Several Phase III studies have now been completed. Sipuleucel-T prolonged survival compared with placebo in asymptomatic or minimally symptomatic patients with mCRPC. Cabazitaxel plus prednisone prolonged survival in patients with mCRPC who progressed during or after docetaxel-based therapy compared with the active agent mitoxantrone, plus prednisone. Multidisciplinary management and optimization of the role and timing of new agents in this evolving treatment continuum will be critical to maximizing patient outcomes. Identification of predictive markers and better gene expression profiling will be critical to tailoring therapies to individual patients and disease states, whereas validated surrogate markers of overall survival will help accelerate drug approval.

Although advanced prostate cancer patients respond very well to front-line androgen deprivation, failure to hormonal therapy most often occurs after a median time of 18-24 months. The care of castration-resistant prostate cancer (CRPC) has significantly evolved over the past decade, with the onset of first-line therapy with docetaxel. Although numerous therapy schedules have been investigated alongside docetaxel, in either first-line or salvage therapy, results were dismal. However, CRPC chemotherapy is currently evolving, with, on the one hand, new agents targeting androgen metabolism and, on the other hand, significant progress in chemotherapy drugs, particularly for second-line therapy. The aim of the present review is to describe the current treatments for CRPC chemotherapy alongside their challengers that might shortly become new standards. In this article, we discuss the most recent data from clinical trials to provide the reader with a comprehensive, state-of-the-art overview of CRPC chemotherapy and hormonal therapy.

The results of cytotoxic therapy in the second-line setting of metastatic castration-resistant prostate cancer have demonstrated that disease is poorly controlled after taxane resistance with a time to progression of 3 months or less. Many trials of second-line chemotherapy have been disappointing. However, most of patients with docetaxel-pretreated castration-resistant disease receive a second-line chemotherapy. Molecular mechanism of castration resistance and docetaxel resistance is resumed, and clinical trials of second-line chemotherapy after docetaxel progression are reviewed. Reintroduction of docetaxel after a drug-free interval is an active treatment in docetaxel-pretreated patients, and only recently a prospective study documented a survival benefit of 2.4 months after second-line taxane-based chemotherapy of metastatic docetaxel-resistant prostate cancer. Although a second-line chemotherapy with a taxane could improve overall survival, a change of biology of castration-resistant prostate cancer after docetaxel is suggested, as inferred by the renewed hormonal sensitivity, whose role on survival remains unknown, and from the activity of antiangiogenic drugs.

There is no proven, effective, standard second-line chemotherapy for castration- and docetaxel-resistant prostate cancer (DRPC). Recent data suggest that carboplatin may be effective in combination with docetaxel in this setting; however, the optimal docetaxel/carboplatin-based regimen is still unclear.

We identified 43 consecutive patients with DRPC treated with carboplatin (AUC5 d1) and docetaxel (35 mg/m(2) d1, 8, 15 q4w i.v.) as a second-line or subsequent salvage chemotherapy until discontinuation of therapy due to disease progression or unacceptable toxicity.

Decreased prostate-specific antigen (> or =50% PSA) was observed in 22/43 (51.2%, 95% CI, 35.5, 66.7%) patients, with > or =90% reduction in 12/43 patients (27.9%). At the time of analysis, the median follow-up time for all patients was 10.4 months. Median progression-free survival (PFS) for all patients was 6.5 months (95% CI 4.1, 8.9), and median overall survival (OS) was 15.8 months (95% CI 12.1, 18.5). In PSA responders, PFS was 9.5 (95% CI 8.2, 19.0) months versus 3.3 (95% CI 2.6, 4.0) months in PSA non-responders (P < 0.0001; hazard ratio (HR) 0.108) and OS was 24.4 months (95% CI 19.5, 29.4) versus 7.8 (95% CI 5.2, 10.3) months (P = 0.001; HR 0.232). Established prognostic factors were associated with survival. This regimen was reasonably well tolerated, with leukopenia/neutropenia as the most common reversible grade 3/4 toxicity (41.9/39.5%).

These data suggest that weekly docetaxel plus carboplatin may be an important therapeutic second-line treatment option for patients with DRPC.