First-line combination treatment with docetaxel plus androgen receptor pathway inhibitor (ARPI) plus androgen deprivation therapy (ADT) or poly(ADP-ribose) polymerase inhibitor (PARPi) plus ARPI plus ADT results in clinically relevant but not statistically significant improvements in progression-free survival (PFS) in patients with metastatic hormone-sensitive prostate cancer (mHSPC), a study has found.
However, none of these intensified regimens provide statistically significant benefit in overall survival (OS) when compared with ARPI plus ADT in the all-comer population, but docetaxel plus ARPI plus ADT has improved OS in the high-volume subgroup.
“The lack of a clear survival advantage in all-comers and the varying certainty of evidence (CoE) support a selective, biomarker-driven or targeted approach,” the investigators said. “Treatment decisions should balance potential oncological gains against distinct toxicity profiles.”
The databases of Medline, Embase, and Web of Science were systematically searched in March 2026 to identify randomized controlled trials (RCTs) evaluating first-line combination therapies for mHSPC, with PFS and/or OS and severe adverse events (AEs) as outcomes of interest. Twenty-three RCTs, including a total of 18,689 patients, met the eligibility criteria. [J Urol 2026;216:336-351]
The investigators conducted frequentist random-effects network meta-analyses, particularly to RCTs involving the all-comer population, and did a systematic review for targeted and biomarker-driven strategies. They also assessed the CoE using the Confidence in Network Meta-Analysis framework.
In the all-comer network meta-analysis, docetaxel plus ARPI plus ADT (hazard ratio [HR], 0.66, 95 percent confidence interval [CI], 0.43‒1.01; CoE: moderate) and PARPi plus ARPI plus ADT (HR, 0.55, 95 percent CI, 0.23‒1.34; CoE: low) demonstrated clinically relevant but statistically nonsignificant PFS compared with ARPI plus ADT.
OS benefit
None of the triplet regimens delivered a statistically significant OS benefit in comparison to ARPI plus ADT, but the combination of docetaxel plus ARPI plus ADT resulted in a significant OS improvement in the high-volume subgroup (HR, 0.76, 95 percent CI, 0.61‒0.95; CoE: high).
The addition of docetaxel or PARPi did not show a statistically significant risk for severe AE. The most frequent severe AEs were hypertension and anaemia. However, substantial imprecisions were noted in the safety estimates, thus a clinically meaningful increase in toxicity cannot be excluded.
“Overall, evidence certainty was downgraded because of risk of bias from open-label designs, clinical inconsistency in prior docetaxel exposure across comparator arms, and imprecision, particularly for PARPi-based regimens because of small sample sizes in phase II data,” the investigators said.
“Targeted and biomarker-driven strategies (AMPLITUDE, CAPItello-281, and PSMAddition) further supported the benefit of intensification in selected or target-positive populations,” they added.
Standard of care
Current international guidelines for mHSPC treatment recommend intensification with ADT plus ARPI with or without docetaxel as standard of care. [https://uroweb.org/guidelines/prostate-cancer; https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf; J Urol 2023;209:1082-1090]
“More recently, the AMPLITUDE, PSMAddition, and CAPItello-281 trials have introduced additional layers of complexity by demonstrating that incorporation of emerging agents—such as PARPis, prostate-specific membrane antigen–directed theranostic therapies, and AKT inhibitors—may further improve clinically relevant outcomes,” the investigators said. [Nat Med 2025;31:4109-4118; Ann Oncol 2026;37:53-68]
“However, the relative magnitude of benefit among these increasingly diverse treatment strategies remains uncertain,” they added.