Table 2.

Pivotal phase III trials published from 2004 to 2020 that have radically changed the therapeutic scenario of metastatic prostate cancer, both in hormone-sensitive and castration-resistant context.

Study [Author, Year]	Treatment	Clinical Setting	OS Benefit	PFS Benefit	Adverse Events of any Grade
TAX 327 [Tannock et al., 2004] [22]	Docetaxel * (vs. mitoxantrone)	mCRPC	18.9 months vs. 16.4 months (p = 0.009)	-	More frequently (dtx vs. mtx): -Alopecia (65% vs. 13%) -Fatigue (53% vs. 35%) -G3/G4 neutropenia (32% vs. 22%) -Diarrhea (32% vs. 10%) -Sensory neuropathy (30% vs. 7%)
SWOG 99–16 [Petrylak et al., 2004] [23]	Docetaxel + estramustine (vs. mitoxantrone)	mCRPC	17.5 months vs. 15.6 months (p = 0.02)	6.3 months vs. 3.2 months (p < 0.001) in terms of TTP	More toxicity due to the addition of estramustine
CHARTEED [Sweeney et al., 2015] [24]	Docetaxel + ADT (vs. ADT alone)	High volume mHSPC	57.6 months vs. 44.0 months (p < 0.001)	33.0 months vs. 19.8 months (p < 0.001) in terms of cPFS	More frequently with dtx + ADT (only high grade described): -Fatigue (4.1%) -Febrile neutropenia (3.8%) -G3/G4 neutropenia (3.1%) -Diarrhea (1%)
TROPIC [De Bono et al., 2010] [25]	Cabazitaxel (vs. mitoxantrone)	mCRPC post- docetaxel	15.1 months vs. 12.7 months (p < 0.0001)	2.8 months vs. 1.4 months (p < 0.0001)	More frequently (caba vs. mtx): -Anemia (97% vs. 81%) -Neutropenia (94% vs. 88%) -Thrombocytopenia (47% vs. 43%) -Diarrhea (47% vs. 11%)
CARD [De Wit et al., 2019] [26]	Cabazitaxel (vs. abiraterone acetate + prednisone or enzalutamide)	mCRPC after docetaxel and abiraterone acetate + prednisone or enzalutamide	13.6 months vs. 11.0 months (p = 0.008)	8.0 months vs. 3.7 months (p < 0.001)	More frequently (caba vs. abi/enza): -Fatigue (53.2% vs. 36.3%) -Diarrhea (39.7% vs. 6.5%) -Infection (33.7% vs. 20.2%) -Musculosketal pain (27.0% vs. 39.5%)
COU-AA-301 [De Bono et al., 2011] [27]	Abiraterone acetate + prednisone (vs. placebo)	mCRPC post- docetaxel	15.8 months vs. 11.2 months (p < 0.001)	5.6 months vs. 3.6 months (p < 0.001) in terms of rPFS	More frequently (abi vs. placebo): -Fatigue (47% vs. 44%) -Nausea (33% vs. 33%) -Back pain (33% vs. 36%) -Anemia (25% vs. 28%)
COU-AA-302 [Ryan et al., 2013] [28,29]	Abiraterone acetate + prednisone (vs. placebo)	mCRPC pre- docetaxel	34.7 months vs. 30.3 months (p = 0.003)	16.5 months vs. 8.3 months (p < 0.001) in terms of rPFS	More frequently (abi vs. placebo): -Fluid retention (30% vs. 23%) -Hypertension (19% vs. 11%) -Hypokalemia (16% vs. 11%) -Cardiac disorders (16% vs. 14%)
LATITUDE [Fizazi et al., 2017] [30]	Abiraterone acetate + prednisone (vs. placebo)	High-risk mHSPC	53.5 months vs. 36.5 months (p < 0.0001)	33.0 months vs. 14.8 months (p < 0.001) in terms of rPFS	More frequently (abi vs. placebo): -Hypertension (37% vs. 22%) -Hypokalemia (20% vs. 4%) -Increased ALT (16% vs. 13%) -Hyperglycemia (13% vs. 11%)
AFFIRM [Scher et al., 2012] [31]	Enzalutamide (vs. placebo)	mCRPC post- docetaxel	18.4 months vs. 13.6 months (p < 0.001)	8.3 months vs. 2.9 months (p < 0.001) in terms of rPFS	More frequently (enza vs. placebo): -Fatigue (34% vs. 29%) -Diarrhea (21% vs. 18%) -Hot flash (20% vs. 10%) -Musculoskeletal pain (14% vs. 10%)
PREVAIL [Beer et al. 2014] [32]	Enzalutamide (vs. placebo)	mCRPC pre- docetaxel	36.0 months vs. 31.0 months (p < 0.001)	65% vs. 14% at 12 months (p < 0.001) in terms of rPFS	More frequently (enza vs. placebo): -Fatigue (52% vs. 35%) -GI events (49% vs. 42%) -Hypertension (18% vs. 4.2%) -Fall (16% vs. 5.1%)
ARCHES [Armstrong et al., 2019] [33]	Enzalutamide + ADT (vs. placebo + ADT)	mHSPC	OS data still immature	NR vs. 19.0 months (p < 0.001)	More frequently (enza vs. placebo): -Hot flash (27.1% vs. 22.3%) -Fatigue (19.6% vs. 15.3%) -Arthralgia (12.2% vs. 10.6%) -Hypertension (8% vs. 5.6%)
ENZAMET [Davis et al., 2019] [34]	Enzalutamide + ADT (vs. 1st generation NSAA + ADT)	mHSPC	80% vs. 72% at 3 years according to Kaplan–Meier estimates (p = 0.002)	68% vs. 41% at 3 years according to Kaplan–Meier estimates (p < 0.001) in terms of cPFS	More frequently (enza vs. 1st generation NSAA): -G2 fatigue (25% vs. 14%) -G3/G4 Hypertension (8% vs. 4%) -G3/G4 Neutropenia (6% vs. 3%)
PROFOUND [De Bono et al., 2020] [35]	Olaparib (vs. abiraterone acetate + prednisone or enzalutamide)	mCRPC (Cohort A: at least one alteration in BRCA1/2, or ATM; cohort B: alterations in any of 12 other prespecified genes)	-Cohort A: 18.5 months vs. 15.1 months (p = 0.02) -Overall population (Cohorts A and B): 17.5 months vs. 14.3 months (p = 0.02)	-Cohort A: 7.4 months vs. 3.6 months (p < 0.001) -Overall population (Cohorts A and B): 5.8 months vs. 3.5 months (p < 0.001)	More frequently (Ola vs. placebo): -Anemia (46% vs. 15%) -Nausea (41% vs. 19%) -Fatigue (41% vs. 32%) -Decreased appetite (30% vs. 18%)

Abbreviations: mHSPC: metastatic hormone-sensitive prostate cancer; mCRPC: metastatic castration-resistant prostate cancer; OS: overall survival; PFS: progression-free survival; cPFS: clinical PFS; rPFS: radiological PFS; TTP: time to progression; ADT: androgen deprivation therapy; dtx: docetaxel; mtx: mitoxantrone; caba: cabazitaxel; abi: abiraterone acetate; enza: enzalutamide; NSAA: –steroidal anti-androgen; ola: olaparib; GI: gastro-intestinal; G: grade; NR: not-reached. *: data presented for the experimental arm in which docetaxel were administered every 3 weeks; TAX-327 trial had an additional arm where patients were treated with weekly docetaxel regimen, not shown in this table.