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.