Treatment Landscape for Patients with Castration-Resistant Prostate Cancer: Patient Selection and Unmet Clinical Needs

Figures & data

Table 1 Phase III Trials in Non-Metastatic Castration Resistant Prostate Cancer (nmCRPC)

	Study Design	Clinical Trial	n	Median Follow-Up (Months)	Median MFS (Months)	Median OS (Months)
Enzalutamide	ENZA vs placebo	PROSPER [10,25]	1401	48	36.6 vs 14.7 (HR 0.29, 95% CI 0.24–0.35, p<0.001	67 vs 56.3 (HR 0.73, 95% CI 0.73, 95% CI 0.61–0.89, p=0.001
Apalutamide	APA vs placebo	SPARTAN [11,26]	1207	52	40.5 vs 16.2 (HR 0.28, 95% CI 0.23–0.35, p<0.001)	73.9 vs 59.9 (HR 0.78, 95% CI 0.78, 95% CI 0.64–0.96, p=0.016
Darolutamide	DARO vs placebo	ARAMIS [12,27]	1509	29	40.4 vs 18.4 (HR 0.41, 95% CI 0.34–0.5, p<0.001)	3 years OS: 83 vs 77% (HR 0.69, 95% CI 0.53–0.88, p=0.003

Abbreviations: ENZA, enzalutamide; APA, apalutamide; DARO, darolutamide; MFS, metastasis free survival; OS, overall survival; HR, hazard ratio; CI, confidence interval; n, number of patients.

Figure 1 Timeline of treatments for mCRPC (year of reported positive pivotal trial). 1,2Tannock, IF et al. N Engl J Med 2004; 3De Bono, J et al. Lancet 2010, 4Oudard, S et al. J Clin Oncol 2017, 5Kantoff, P.W. et al. N Engl J Med. 2010; 6De Bono, J et al. N Engl J Med. 2011, 7Ryan, CJ et al. N Engl J Med. 2013, 8Scher, HI et al. N Engl J Med 2012; 9Beer, TM et al. N Engl J Med 2014, 10Parker, C et al. N Engl J Med. 2013, 11Nilsson S et al. Ann Oncol. 2016; 12De Bono, J et al. N Engl J Med 2020;13Sartor O et al. N Engl J Med. 2021. *Approval EMA withdrawn, not available in Europe; +symptomatic, bone only, LN<3cm, visceral mets. excluded; approval §EMA: BRCA1,2 FDA: HRD panel PROfound, Rucaparib (FDA only); **FDA only approval, not EMA.

Table 2 Phase III Trials Reporting Overall Survival Benefit in Metastatic Castration Resistant Prostate Cancer (mCRPC) Setting

	Study Design	Clinical Trial	n	Median OS (Months)	Endpoints
Docetaxel	DOCE 60 mg/m2 + Estramustine/PRED vs MTX/PRED	SWOG 99–16 [42]	770	17.5 vs 15.6 (HR 0.8, 95% CI 0.67–0.97, p=0.02)	DOCE/Estramustine/PRED improves OS
	DOCE 75 mg/m2 vs DOCE 30 mg/m2 weekly vs MTX	TAX327 [13]	1006	18.9 vs.17.4 vs 16.5. HR (DOCE 75 mg/m2 vs DOCE 30 mg/m2 weekly vs MTX) 0.83, 95% CI 0.7–0.99, p=0.04	DOCE improves OS
Cabazitaxel	CBZ vs MTX	TROPIC [14]	755	15.1 vs 12.7 (HR 0.7, 95% CI 0.59–0.83, p<0.0001)	CBZ improves OS after DOCE-based therapy
	CBZ vs ENZA or AB+PRED	CARD [50]	255	13.6 vs 11 (HR 0.64, 95% CI 0.46–0.89, p=0.008)	CBZ improves OS over second ARTA
Abiraterone (2nd-line after DOCE)	AB+PRED vs Placebo + PRD	COU-301 [15]	1195	14.8 vs 10.9 (HR 0.65, 95% CI 0.54–0.77, p<0.001	AB+PRED improves OS after DOCE treatment
Abiraterone (TX naive mCRPC) asymptomatic, mildly symptomatic, no visceral mets	AB+PRED vs Placebo + PRED	COU-302 [43]	1088	34.7 vs 30.3 (HR 0.75, 95% CI 0.61–0.93, P=0.01)	AB+PRED improves OS in CHT naive patients
Enzalutamide	ENZA vs Placebo	AFFIRM [16]	1199	18.4 vs 13.6 (HR 0.63, 95% CI 0.53–0.75, p<0.001)	ENZA improves OS after CHT
Enzalutamide (TX naive mCRPC) asymptomatic or mildly symptomatic	ENZA vs Placebo	PREVAIL [44]	1717	32.4 vs 30.2 (HR 0.71, 95% CI 0.6–0.84, p<0.001	ENZA improves OS in CHT naive patients
Radium-223	Ra-223 vs Placebo	ALSYMPCA [17]	921	14.9 vs 11.3 (HR 0.7, 95% CI 0.55–0.88, p=0.002	Ra-223 improves OS
Olaparib	Olaparib vs ENZA or AB + PRED	PROFOUND [19]	387 Cohort A (BRCA1, BRCA2, ATM alteration= 245 Cohort B (all other 12 prespecified HRD defects) = 142	Cohort A: 19.1 vs 14.7 (HR 0.69, 95% CI 0.5–0.97, p=0.02) Cohort B: 14.1 vs 11.5 (HR 0.96, 95% CI 0.63–1.49)	Olaparib improves OS over second ARTA in patients with BRCA1, BRCA2 and ATM mutation Olaparib does not improve OS over second ARPI in patients with HRD defects other than BRCA1, BRCA2, ATM
^177-Lutetium-PSMA-617	^177-Lutetium-PSMA-617 plus protocol-permitted SOC vs protocol-permitted SOC	VISION [18]	617	15.3 vs 11.3 (HR 0.62, 95% CI 0.52–0.74; P<0.001)	^177-Lutetium-PSMA-617 improves OS when added to systemic treatment according to VISION protocol
Sipuleucel-T	Sipuleucel-T vs placebo	IMPACT [45]	512	25.8 vs 21.7 (HR 0.78, 95% CI 0.61–0.98; p=0.03	Sipuleucel-T improves OS

Abbreviations: DOCE, docetaxel; PRED, prednisone; MTX, mitoxantrone; OS, overall survival; CBZ, cabazitaxel; AB, abiraterone; mCRPC, metastatic castration-resistant prostate cancer; CHT, chemotherapy; Ra-223, radium-223; GCSF, granulocyte stimulating factor; ARPI, androgen-receptor pathway inhibitor; HRD, homologous repair-deficiency; SOC, standard of care; HR=hazard ratio; CI, confidence interval; n, number of patients; PSMA, prostate-specific membrane antigen; BRCA, breast cancer gene; ATM, ataxia telangiectasia mutated; ENZA, enzalutamide; TX, treatment.

Table 3 Recently Reported Trials in Metastatic Castration Resistant Prostate Cancer (mCRPC)

NCT Number (Trial Name)	Phase	Setting	Treatment Arms	Primary Endpoints	Results
NCT03072238 (IPATential150)	3	mCRPC 1st-line	ADT+Abiraterone+Ipatasertib vs ADT+Abiraterone+Placebo	rPFS investigator-assessed in the PTEN-loss-by-IHC population and in the intention-to-treat population	rPFS PTEN-loss by IHC: 18.5 months vs 16.5 months, HR 0.77, 95% CI 0.61–0.98; p=0.034 rPFS intention-to-treat population: 19.2 months vs 16.6 months, HR 0.84, 95% CI 0.71–0.99, p=0.043
NCT02257736 (ACIS)	3	mCRPC 1st-line	ADT+Abiraterone+Apalutamide vs ADT+Abiraterone+Placebo	rPFS intention-to-treat population	rPFS (median follow-up 25.7 months): 22.6 months vs 16.6 months, HR 0.69, 95% CI 0.58–0.83; p<0.0001 rPFS updated analysis (median follow-up 54.8 months): 24.0 months vs 16.6 months, HR 0.70, 95% CI 0.60–0.83; p<0.0001
NCT03016312 (IMbassador250)	3	mCRPC 2nd-line after docetaxel	ADT+Enzalutamide+Atezolizumab vs ADT+Enzalutamide	OS	OS: 15.2 months vs 16.6 months, HR 1.12, (95% CI 0.91, 1.37); p = 0.28
NCT03732820 (PROPEL)	3	mCRPC 1st-line Prior Docetaxel in mHSPC allowed Prior ARTA in mHSPC or nmCRPC allowed if stopped ≥ 12 months prior	ADT+Abiraterone+Olaparib vs ADT+Abiraterone+Placebo	rPFS investigator-assessed	rPFS investigator assessed: 24.8 months vs 16.6 months, HR 0.66; (95% CI 0.54–0.81), p<0.0001 rPFS blinded independent central review: 27.6 months vs 16.4 months, HR 0.61, 95% CI 0.49–0.74, p<0.0001 OS: immature data (23% events), HR 0.86, 95% CI 0.66–1.12 ORR: 58% vs 48%
NCT03748641 (MAGNITUDE)	3	mCRPC 1st-line HRR± vs HRR- prospectively assessed Prior Docetaxel in mHSPC allowed Prior ARTA in mHSPC or nmCRPC allowed if stopped ≥ 12 months; prior abiraterone allowed if ≤ 4 months	ADT+Abiraterone+Niraparib vs ADT+Abiraterone+Placebo	rPFS central independent blinded review	rPFS: central independent blinded review HRR-: stopped enrollment after futility analysis (defined HR > 1.0) after 233 patients, HR 1.09 HRR±: 16.5 months vs 13.7 months, HR 0.75, 95% CI 0.57–0.97, p<0.0001 OS: immature data (27% events), RR: 2.13 ORR: 60% vs 28%

Abbreviations: mCRPC, metastatic castration-resistant prostate cancer; CHT, chemotherapy; ARPI, androgen-receptor pathway inhibitor; ADT, androgen-deprivation therapy; PTEN, phosphatase and tensin homolog; IHC, immunohistochemistry; rPFS, radiographic progression-free survival; CI, confidence interval; HR, hazard ratio; mHSPC, metastatic hormone-sensitive prostate cancer; nmCRPC, non-metastatic castration-resistant prostate cancer; OS, overall survival; ORR, overall response rate; HRR, homologous recombination repair; RR, relative risk.

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