End points of clinical trials in metastatic castration-resistant prostate cancer: A systematic review

Table 1 Prostate cancer working group-2 suggested outcome measures for metastatic castration-resistant prostate cancer trials

Variable	Outcome measure
Progression criteria
PSA	A favorable effect on PSA may be delayed for 12 wk or more, even for a cytotoxic drug Decline from baseline. PSA increase ≥ 25% and ≥ 2 ng/mL above the nadir, and which is confirmed by a second value 3 or more weeks later No decline from baseline. PSA progression ≥ 25% and ≥ 2 ng/mL after 12 wk
Bone metastases	The appearance of ≥ 2 new lesions, and, for the first reassessment only, a confirmatory scan performed 6 or more weeks later that shows a minimum of 2 or more additional new lesions. The date of progression is the date of the first scan showing the changes
Soft tissue lesions	RECIST criteria, with the additional requirement that progression at first assessment is confirmed by a second scan 6 or more weeks later. For some treatments, a lesion may increase in size before it decreases
Symptoms	Consider independently of other outcome measures. Document pain/analgesia at entry and measure repeatedly at 3- to 4-wk intervals. Ignore early changes ( ≤ 12 wk) in pain or HRQOL in the absence of compelling evidence of disease progression.
	Confirm progression of pain or HRQOL end points ≥ 3 wk later
Response criteria
PSA	Ignore early rises (prior to 12 wk) in determining PSA response Record the percent change from baseline at 12 wk, and the maximal change at any time using a waterfall plot
Bone metastases	Record outcome as new lesions or no new lesions. If at the first scheduled reassessment there are not new lesions, continue therapy; if there are new lesions, perform a confirmatory scan 6 or more weeks later and only where new lesions are present stop therapy due to progressive disease
Soft tissue lesions	RECIST criteria, with some caveats:
	only report changes in lymph nodes that were ≥ 2 cm in diameter at baseline; record changes in nodal and visceral soft tissue sites separately; record complete elimination of disease at any site separately; confirm favorable change with second scan; record changes using a waterfall plot
Symptoms	Consider independently of other outcome measures. Document pain/analgesia at entry and measure repeatedly at 3- to 4-wk intervals. Ignore early changes ( ≤ 12 wk) in pain or HRQOL in the absence of compelling evidence of disease progression Confirm response of pain or HRQOL end points ≥ 3 wk later

PSA: Prostate-specific antigen; RECIST: Response evaluation criteria in solid tumors; HRQOL: Health-related quality of life.

Table 2 Characteristics of randomized clinical trials including overall survival as the primary end point after first-line and/or second-line medical treatment of metastatic castration-resistant prostate cancer

Trial	Arms	No. pts	Publication year	Main conclusion	Median OS
LSG Trial[18]	LIA	160	1998	After adjustment for baseline prognostic factors, HR for OS favored the first arm	10.3 mo
	CPA	161			10.3 mo
CALGB 9182[19]	MXN + HDC	119	1999	Better PSA-RR and PFS in the first arm	12.3 mo
	HDC	123			12.6 mo
HOG/FNC Trial[20]	VBL + ESM	95	1999	Better PSA-RR and PFS in the first arm	11.9 mo
	VBL	98			9.2 mo
SWOG 9916[6]	DOC + ESM	338	2004	Longer OS in the first arm	17.51 mo
	MXN + PDN	336			15.6 mo
TAX327[5]	MXN + PDN	337	2004	DOC-based chemotherapy is the new standard first-line treatment of mCRPC	16.5 mo
	DOC + PDN	335			18.91 mo
	wDOC + PDN	334			17.4 mo
3SPARC[21]	SPT + PDN	635	2009	Better PSA-RR in the first arm	61.3 wk
	Placebo + PDN	315			61.4 wk
2TROPIC[7]	CBZ + PDN	378	2010	CBZ-based therapy is effective in mCRPC progressing to DOC	15.11 mo
	MXN + PDN	377			12.7 mo
IMPACT[22]	SIP-T	341	2010	Similar results	25.81 mo
	Placebo	171			21.7 mo
2COU-AA-301[8]	ABI + PDN	797	2011	ABI hormonal therapy is effective in mCRPC progressing to DOC	14.81 mo
	Placebo + PDN	398			10.9 mo
ASCENT-2[23]	DOC + DN101	477	2011	DN101 is inferior to PDN	17.8 mo
	DOC + PDN	476			20.21 mo
CALGB 90401[24]	DOC + PDN + BEV	524	2012	Better PSA-RR and PFS in the first arm	22.6 mo
	DOC + PDN + Placeb	526			21.5 mo
2AFFIRM[9]	ENZ	800	2012	ENZ hormonal therapy is effective in mCRPC progressing to DOC	18.41 mo
	Placebo	399			13.6 mo
ENTHUSE M1C[25]	DOC + ZBT	524	2013	Similar results	20.0 mo
	DOC + Placebo	528			19.2 mo
3ALSYMPCA[10]	Radium-223	614	2013	Radium-223 effective in mCRPC with painful bone metastases	14.91 mo
	Placebo	307			11.3 mo

¹Statistically significant difference;

²Trial of second-line medical treatment;

³Trial of first or second-line medical treatment. ABI: Abiraterone; BEV: Bevacizumab; CBZ: Cabazitaxel; CPA: Cyproterone acetate; DN101: High-dose calcitriol; DOC: Docetaxel; ENZ: Enzalutamide; ESM: Estramustine; HDC: Hydrocortisone; HR: Hazard ratio; LIA: Liarozole; mCRPC: Metastatic castration-resistant prostate cancer; MXN: Mitoxantrone; OS: Overall survival; PDN: Prednisone; PFS: Progression-free survival; PSA-RR: Prostate-specific antigen response rate; SIP-T: Sipuleucel-T; SPT: Satraplatin; VBL: Vinblastine; wDOC: Weekly-docetaxel; ZBT: Zibotentan.

Table 3 Characteristics of randomized clinical trials including time-to-event measures as the primary end point after first-line medical treatment of metastatic castration-resistant prostate cancer

Trial	Arms	No. pts	Publication year	End point	Result(mo)
DAPROCA 9002[26]	ESM	61	1997	TTSP	2.2
	Placebo	68			5.0
EORTC[27]	FLT	100	2001	TTP	2.3
	PDN	101			3.4
USOR[28]	MXN + PDN	56	2002	TTTF	8.11
	PDN	63			4.1
Vinorelbine Trial[29]	VNR + HDC	206	2004	PFS	3.71
	HDC	208			2.8
UCSF[30]	SIP-T	82	2006	TTP	11.7
	Placebo	45			10.0
Atrasentan Trial[31]	ATR	408	2007	TTP	HR = 0.89
	Placebo	401
PROSTVAC[32]	PROSTVAC	82	2010	PFS	3.8
	Placebo	40			3.7
PROSTY Trial[33]	DOC three-weekly	184	2013	TTTF	4.9
	DOC two-weekly	177			5.61

¹Statistically significant difference. ATR: Atrasentan; DOC: Docetaxel; ESM: Estramustine; FLT: Flutamide; HDC: Hydrocortisone; HR: Hazard ratio; MXN: Mitoxantrone; PDN: Prednisone; PFS: Progression-free survival; PROSTVAC: Vaccinia-PSA-TRICOM and Fowlpoc-PSA-TRICOM; SIP-T: Sipuleucel-T; TTP: Time to progression; TTSP: Time to subjective progression; TTTF: Time to treatment failure; VNR: Vinorelbine.

Table 4 Disease-progression-related events used to define secondary end points in randomized trials of metastatic castration-resistant prostate cancer

Progression event	Trial number	Ref.
Clinical	2	[26,34]
Pain	2	[25,35]
Skeletal-related events	4	[8-10,23]
Radiological	7	[6,8,9,22,24,25,36]
Prostate-specific antigen	6	[8-10,24,25,31]
Alkaline phosphatase	2	[10,31]
Mixed	9	[7,19,20,21,28,33,37-39]

Table 5 Characteristics of randomized clinical trials including radiologic or serological response measures as the primary end point after first line medical treatment of metastatic castration-resistant prostate cancer

Trial	Arms	No. pts	Publication year	Response-related outcome	Response rate (%)
CALGB 9181[40]	MA 160 mg/die	73	2000	MRR	3%
	MA 640 mg/die	76			3%
INT 0159[36]	SUR 3,1	128	2002	PSA-RR/RRR	24%/9%
	SUR 5,3	124			28%/7%
	SUR 7,6	120			34%/15%
ECOG 3882[34]	DOXO + DES	74	2003	MRR	63%1
	DOXO	76			27%
CALGB 9583[41]	AWD + KET + HDC	128	2004	MRR	27%1
	AWD	132			11%
Belgian Trial[38]	DOC + PDN + ESM	71	2008	PSA-RR	41%
	DOC + PDN	69			25%
NHS Trial[39]	DEX + ASP + DES	136	2011	PSA-RR	64%
	DEX + ASP	133			68%

¹Statistically significant difference. ASP: Aspirin; AWD: Anti-androgen withdrawal; DES: Diethylstilbestrol; DEX: Dexamethasone; DOXO: Doxorubicin; ESM: Estramustine; HDC: Hydrocortisone; KET: Ketoconazole; MA: Medroxyprogesterone acetate; MRR: Mixed response rate; PDN: Prednisone; PSA-RR: Prostate-specific antigen response rate; RRR: Radiologic response rate; SUR: Suramine.

Table 6 Characteristics of randomized clinical trials including clinical response measures as the primary end point after first line medical treatment of metastatic castration-resistant prostate cancer

Trial	Arms	No. pts	Publication year	PROmeasure	Palliative response rate (%)
Canadian Trial[4]	MXN + PDN	80	1996	Palliative response (moore)	291
	PDN	81			12
SIG-1 Trial[37]	SUR + HDC	228	2000	Palliative response (BPI + analgesics)	431
	Placebo + HDC	230			28
NCIC PR06[35]	MXN + PDN + CLD	104	2003	Palliative response (moore)	46
	MXN + PDN + Placebo	105			39

¹Statistically significant difference. BPI: Brief pain inventory; CLD: Clodronate; HDC: Hydrocortisone; MXN: Mitoxantrone; PDN: Prednisone; PRO: Patient-reported outcome; SUR: Suramine.

Table 7 Disease-control/response related events used to define secondary end points in randomized trials of metastatic castration-resistant prostate cancer

Progression event	Trial number	Ref.
Clinical	1	[27]
Pain	5	[7-9,18,21]
Radiological	11	[4,5,7,19,20,21,24,26,28,37,38]
Prostate-specific antigen	19	[4,5,7,8,19-22,24,25,27-29,33,35, 37,38,40,41]
Alkaline phosphatase	1	[10]
Immunity	1	[32]