Metastatic hormone-sensitive prostate cancer: How should it be treated?

Table 1 Characteristics of the randomized phase 3 trials of second-generation antihormonal treatments in metastatic hormone-sensitive prostate cancer

Trial	Treatment	n	Inclusion criteria	Stratification	Main objective	Secondary objectives
LATITUDE (Fizazi K et al[16]) 2017	ABIRATERONE 1000 mg + PREDNISONE 5 mg + ADT; PLACEBO + ADT	597; 602	High risk con ≥ 2 factors: (1) Gleason 8-10; (2) ≥ 3 bone METS; (3) Evaluable visceral METS; and (4) ECOG PS ≤ 2	Visceral METS (yes/no); ECOG PS (0, 1/2)	OSrPFS	Time to pain progression; Time to PSA progression; Development of skeletal events; Time to chemotherapy; Time to new treatment; QoL
STAMPEDE (James et al[17])1 2017	ABIRATERONE 1000 mg + PREDNISONE 5 mg + ADT; ADT	502; 500	Presence of METS	ECOG PS (0/1, 2); AGE (< 70/≥ 70); Use of steroids (yes/no); Research centre; Indication for RT (yes/no); Type of ADT	OS	PFS; Failure-free survival; Cancer-specific survival; Time to skeletal events; Toxicity; QoL
ENZAMET (Davis et al[13]) 2019	ENZALUTAMIDE 160 mg + ADT; ANTIANDROGENS (bicalutamide, flutamide or nilutamide) + ADT	563; 562	Low and high volume defined: (1) Visceral METS; and (2) ≥ 4 bone METS, at least 1 outside vertebral column or pelvis. ECOG PS ≤ 2	Volume (high/low); Docetaxel (yes/no); Comorbidities (0-1/2-3); Antiresorptive treatment (yes/no); Research centre	OS	PFS; PSA response; Adverse effects; QoL; Cost-effectiveness
TITAN (Chi et al[15]) 2019	Apalutamide 240 mg + ADT; PLACEBO + ADT	525; 527	LOW AND HIGH VOLUME DEFINED:(1) Visceral METS + ≥ 1 bone METS; and (2) ≥ 4 bone METS, at least 1 outside vertebral column or pelvis. ECOG PS 0-1; ≥ 1 bone METS on bone scan	Gleason (≤ 7/≥ 8); Docetaxel (yes/no); Geographic region	OS; rPFS	Time to pain progression; Time to opioids; Time to skeletal events; Time to chemotherapy; Time to PSA progression; Survival to 2nd progression; Time to symptomatic local progression; QoL
ARCHES (Armstrong et al[14]) 2019	ENZALUTAMIDE 160 mg + ADT; PLACEBO + ADT	574; 576	ECOG PS 0-1; low and high volume defined:(1) Visceral METS; and (2) ≥ 4 bone METS, at least 1 outside vertebral column or pelvis	Volume (high/low); Docetaxel (no/0-5 cycles/≥ 6)	rPFS; Evaluated at 24 wk	Time to PSA progression; Time to skeletal events; Time to new treatment; Undetectable PSA; Objective response rate; OS; Time to worsening of urinary symptoms; Time to pain progression; Time to castration-resistance; Time to QoL worsening; PROS

¹Only patients with metastases. ADT: Androgen deprivation therapy; METS: Metastases; OS: Overall survival; PROs: Patient-reported outcomes; PS: Performance status; PSA: Prostate-specific antigen; QoL: Quality of life; rPFS: Radiographic progression-free survival; RT: Radiotherapy.

Table 2 Survival and toxicity results of the phase 3 randomized clinical trials of second-generation antihormonal treatments in metastatic hormone-sensitive prostate cancer

Trial	Follow-up in mo	Main results	Quality of life	Toxicity
LATITUDE	51.8	Reduced mortality risk by 34% with abiraterone (P < 0.001); OS at 3 yr (66% vs 49%); median OS (53.3 mo vs 36.5 mo). Reduction in risk of radiographic progression by 53% with abiraterone (P < 0.001) (33 mo vs 14.8 mo)	Abiraterone improved all QoL-related parameters	Toxicity grade 3-4: (1) Abiraterone: 63%; (2) Placebo: 48%. Treatment-related deaths: (1) Abiraterone: 5%; and (2) Placebo: 4%
STAMPEDE	40	Reduction in mortality risk of 39% with abiraterone (P < 0.001). Reduction in risk of progression of 69% with abiraterone (P < 0.001). Treatment benefit in all patients according to risk group and disease volume	-	Toxicity grade ≥ 3: (1) Abiraterone: 47%; and (2) ADT: 33%
ENZAMET	33	Reduction in mortality risk by 67% with enzalutamide (P = 0.002). 3-yr OS (82% vs 72%)	No SD	Toxicity grade ≥ 3: (1) Enzalutamide: 58%; and (2) AA: 43%
TITAN	22.7	Reduction in risk of radiographic progression or death by 52% with apalutamide (P < 0.001). 2-yr rPFS (68.2% vs 47.5%). Reduction in mortality risk of 33% with apalutamide (P = 0.005). 2-yr OS (82.4% vs 73.5%). Treatment benefit in all patients according to disease volume, significant in rPFS and OS in high-volume disease	No SD	Toxicity grade 3-4: (1) Apalutamide: 42.2%; and (2) Placebo: 40.8%. Treatment-related deaths: (1) Apalutamide: 1.9%; and (2) Placebo: 3%
ARCHES	14.4	Reduction in risk of radiographic progression or death of 61% with enzalutamide (P < 0.001) (NR vs 19 mo). OS (P = 0.336). Benefit in rPFS in both high and low volume disease	No SD	No SD. Treatment-related deaths: (1) Enzalutamide: 2.4%; and (2) Placebo: 1.7%

AA: First-generation antiandrogens; ADT: Androgen deprivation therapy; NR: Not reached; OS: Overall survival; QoL: Quality of life; rPFS: Radiographic progression-free survival; SD: Statistical differences.