Comparative effectiveness of apalutamide‐, abiraterone‐, and enzalutamide‐based doublets in mHSPC

BACKGROUND AND OBJECTIVE: Treatment of metastatic hormone-sensitive prostate cancer (mHSPC) has evolved from androgen-deprivation therapy (ADT) alone to combination therapy with androgen receptor pathway inhibitors. Although apalutamide (APA), abiraterone (ABI), and enzalutamide (ENZA) improve outcomes when added to ADT, direct comparative trials between androgen receptor pathway inhibitor-based doublets are lacking. METHODS: Our systematic search was conducted on 22 September 2025, in PubMed, Embase, and the Cochrane Library databases. Studies including patients with mHSPC treated with APA, ABI, or ENZA plus ADT were eligible if they contained real-world data and reported at least one outcome: overall survival (OS), PSA50, PSA90, PSA ≤0.2 ng/mL, time to castration-resistant prostate cancer, biochemical progression-free survival, grade ≥3 adverse events, or treatment discontinuation (TDC). Pooled hazard ratios (HRs) and odds ratios (ORs) were calculated using inverse variance random-effects models. KEY FINDINGS AND LIMITATIONS: In total, 17 retrospective studies comprising 18 626 patients were included. Compared with ABI, APA was associated with improved OS (HR 1.27; 95% confidence interval [CI] 1.09-1.47; P = 0.002), PSA90 (OR 0.70; 95% CI 0.54-0.91; P = 0.019), PSA <0.2 ng/mL (OR 0.49; 95% CI 0.25-0.95; P = 0.039), and castration-resistant prostate cancer (HR 1.40; 95% CI 1.05-1.88; P = 0.023). APA also demonstrated higher PSA90 response rates than ENZA (OR 0.67; 95% CI 0.5-0.9; P = 0.017). TDC due to adverse events was lower with ABI than with APA (OR 0.56; 95% CI 0.37-0.86; P = 0.029), with no significant difference between ENZA and APA (P = 0.10). CONCLUSIONS AND CLINICAL IMPLICATIONS: In real-world settings, APA-based doublets were associated with more favourable efficacy outcomes with ABI, whereas ABI- and ENZA-based regimens were associated with lower TDC rates. ABI and ENZA demonstrated comparable efficacy and safety profiles, supporting individualized ARPI selection in mHSPC.