Comparative efficacy and safety of systemic therapies in high-risk hormone-sensitive prostate cancer: A network meta-analysis of 13 phase III randomized trials.

5081 Background: Treatment intensification improves survival in hormone-sensitive prostate cancer (HSPC). However, direct comparisons between triplet therapies consisting of androgen-deprivation therapy, docetaxel, and an androgen receptor pathway inhibitor (ADT+Docetaxel+ARPI) and ARPI doublets are limited. In addition, available evidence remains fragmented between high-risk non-metastatic (nmHSPC) and metastatic (mHSPC) disease states. We conducted a network meta-analysis (NMA) to rank treatment regimens and inform clinical decision-making. Methods: We analyzed 13 phase III RCTs including approximately 13,000 patients with high-risk HSPC, encompassing metastatic and high-risk non-metastatic disease. Treatment strategies included ADT alone, docetaxel (DOC), abiraterone (ABI), enzalutamide (ENZ), apalutamide (APA), darolutamide (DARO), and triplet combinations. A frequentist random-effects NMA was performed with overall survival (OS) as the primary endpoint. Secondary efficacy endpoints included progression-free survival (PFS) and time to castration resistance (TTCR). Safety was assessed using treatment-emergent grade ≥3 AEs, assuming network transitivity. Results: For the primary endpoint (OS), triplet therapies ranked highest, including ADT+DOC+DARO (HR 0.55 [95% CI 0.43–0.69]) and ADT+DOC+ABI (HR 0.60 [95% CI 0.45–0.81]) compared with ADT alone. ARPI doublets also demonstrated robust OS benefits, including ABI (HR 0.63 [0.58–0.69]), APA (HR 0.67 [0.51–0.89]) and ENZ (HR 0.69 [0.51–0.94]). No statistically significant OS difference was observed between triplets and ARPI doublets, although triplets numerically favored higher efficacy. For PFS (I² = 86.5%), triplet therapies remained superior, with ADT+DOC+DARO showing the greatest benefit (HR 0.24 [0.13–0.45]), followed by the ENZ doublet (HR 0.40 [0.27–0.60]). Secondary endpoints (TTCR, PSA-PFS) consistently favored ARPI-based regimens. Regarding safety, triplet therapies significantly increased the odds of Grade ≥3 AEs versus ADT (OR ~2.6–3.7), driven primarily by docetaxel-associated fatigue and ABI-related hypertension. Conversely, APA, ENZ, and DARO doublets demonstrated favorable safety profiles, with no significant increase in overall Grade ≥3 AEs compared with ADT alone (ORs 1.02–1.06). Benefits were consistent across nmHSPC and mHSPC subgroups (p for interaction = 0.66). Conclusions: Triplet therapy represents the efficacy standard for fit patients with high-volume mHSPC. However, ARPI doublets offer a compelling alternative with comparable survival benefits and a superior safety profile, making them the preferred choice for high-risk nmHSPC and patients prioritizing tolerability. Clinical selection should stratify based on disease volume and fitness for docetaxel-associated toxicity.