Table 1.

Phase 3 randomized clinical trials in nmCRPC.

		SPARTAN	PROSPER	ARAMIS
Antiandrogen		Apalutamide	Enzalutamide	Darolutamide
STUDY DESIGN	Inclusion criteria	-M0 N0–1 CRPC -PSA rising -PSAdt ≤ 10 mo -PSA ≥ 2 ng/mL	-M0 N0 CRPC -PSA rising -PSAdt ≤ 10 mo -PSA ≥ 2 ng/mL	-M0 N0–1 CRPC -PSA rising -PSAdt ≤ 10 mo -PSA ≥ 2 ng/mL
	Stratification factors	-PSA-dt > 6 vs. ≤6 mo -Prior use of bone-sparing agents -Nodal disease (N0 vs. N1)	-PSA-dt > 6 vs. ≤6 mo -Prior use of bone-sparing agents	-PSA-dt > 6 vs. ≤6 mo -Use of osteoclast-targeted therapy at randomization
	Primary endpoint	MFS, defined as time from randomization to the first detection of distant metastasis on imaging or death from any cause	MFS, defined as the time from randomization to radiographic progression, or death from any cause between randomization and 112 days after drug discontinuation without evidence of radiographic progression	MFS, defined as the time from randomization to confirmed evidence of distant metastasis on imaging or death from any cause
	Secondary endpoints	-Time to metastasis -PFS -Time to symptomatic progression -OS -Time to chemotherapy	-TTPP -PSA response rate -Time to use of new antineoplastic agent -Quality of life -OS -Safety	-OS -Time to pain progression -Time to first symptomatic SRE -Time to first cytotoxic therapy
POPULATION	Patients	Total randomized: n = 1207 Apalutamide + ADT (n = 806) vs. Placebo + ADT (n = 401)	Total randomized: n = 1401 Enzalutamide + ADT (n = 933) vs. Placebo + ADT (n = 468)	Total randomized: n = 1509 Darolutamide + ADT (n = 955) vs. Placebo + ADT (n = 554)
	Median PSA-dt	Experimental: 4.4 mo Placebo: 4.5 mo	Experimental: 3.8 mo Placebo: 3.6 mo	Experimental: 4.4 mo Placebo: 4.7 mo
	Nodes positivity	16.5% vs. 16.2% (placebo)	–	17% vs. 29% (placebo)
	Median FU	52 mo (interim 20.3 mo *)	48 mo (interim 16.8 mo *)	29 mo (interim 17.9 mo *)
EFFICACY	MFS	40.5 mo vs. 16.2 mo (placebo) HR 0.28 (95% CI 0.23–0.35), p < 0.001 *	36.6 mo vs. 14.7 mo (placebo) HR 0.29 (95% CI 0.24–0.35), p < 0.001 *	40.4 mo vs. 18.4 mo (placebo) HR 0.41 (95% CI, 0.34–0.50), p < 0.001 *
	TTPP	40.5 vs. 3.7 mo (placebo) HR 0.07 (95% CI 0.06–0.09)	37.2 mo vs. 3.9 mo (placebo) HR 0.07 (95% CI 0.05–0.08) *	33.2 mo vs. 7.3 mo (placebo) HR 0.13 (0.11–0.16) *
	PFS	40.5 mo vs. 14.7 mo (placebo) HR 0.29 (95% CI 0.24–0.36) *	Not reported	36.8 mo vs. 14.8 mo placebo HR 0.38 (0.32–0.45) *
	PFS2	55.6 mo vs. 41.2 mo (placebo) HR 0.55 (95% CI 0.46–0.66)	Not reported	Not reported
	Time to symptomatic progression	HR 0.57 (0.44–0.73) p < 0.0001 favoring apalutamide	Not reported	HR 0.65 (0.53–0.79) (pain progression)
	Time to first chemotherapy	HR 0.63 (0.49–0.81) favoring apalutamide	HR 0.54 (0.44–0.67) favoring enzalutamide	HR 0.58 (0.44–0.76) favoring darolutamide
	OS	73.9 vs. 59.9 mo (placebo) HR 0.78 (95% CI 0.64–0.96), p = 0.016	67.0 mo vs. 56.3 mo HR 0.73 (95% CI 0.61–0.89), p = 0.001	40.4 mo vs. 18.4 mo HR 0.69 (0.53–0.88), p = 0.003
SAFETY	Median duration of treatment	32.9 mo vs. 11.5 mo (placebo)	33.9 mo vs. 14.2 mo (placebo)	25.8 mo vs. 11.6 mo (placebo)
	AEs profile	SAEs: 36% vs. 25% (placebo); AEs leading to drug discontinuation: 15% vs. 7.3%; AEs with death 3% vs. 0.5%	SAEs: 40% vs. 22% (placebo); AEs leading to drug discontinuation: 17% vs. 9%; AEs with death 5% vs. 1%	SAEs: 26.1% vs. 21.8% (placebo); AEs leading to drug discontinuation: 8.9% vs. 8.7%; AEs with death 4% vs. 3.4%
	Most frequent ≥ 3 AEs	Hypertension: 16% vs. 12% Skin rash: 5.2% vs. 0.3% Fracture: 4.9% vs. 1.0% Falls: 2.7% vs. 0.8%	Hypertension: 6% vs. 2% Fatigue: 4% vs. 1% Major cardiovascular events: 4% vs. 2% *	Hypertension: 3.5% vs. 2.3% Coronary-artery disorders: 2% vs. 0.4% Cardiac arrhythmia: 1.8% vs. 0.7%
Bibliography		[18,21]	[22,26]	[27,30]

AEs: adverse events; FU: follow up; MFS: metastasis-free survival; mo: months; OS: overall survival; PD: progressive disease; PFS: progression-free survival; PSA-dt: prostate-specific antigen doubling time; SRE: skeletal-related event; TTPP: time to PSA progression; * Data from planned primary analysis.