Androgen Synthesis Inhibitors vs Androgen Receptor Inhibitors and Survival in Metastatic Hormone-Sensitive Prostate Cancer

Importance In metastatic hormone-sensitive prostate cancer (mHSPC), randomized clinical trials directly comparing androgen deprivation therapy intensification using androgen synthesis inhibitors (ASIs) vs next-generation androgen receptor inhibitors (ARIs) are lacking. Objective To compare the outcomes associated with ASI vs ARI intensification therapy among patients with mHSPC in community or academic clinical practices. Design, Setting, and Participants This was a retrospective cohort study of patients diagnosed with mHSPC between February 4, 2013, and April 29, 2024, with follow-up through the July 2024 data cut, providing a median (IQR) follow-up of 25.6 (24.5-26.6) months. Patient-level data were extracted from the nationwide US-based Flatiron Health electronic health record–derived deidentified research database of community and academic practices. Patients with evidence of an mHSPC diagnosis initiating treatment with an ASI (abiraterone acetate) or ARI (apalutamide or enzalutamide) within 3 months prior to or 6 months after an mHSPC diagnosis were eligible. Patients with prior docetaxel receipt were excluded. Exposure Treatment with an ASI vs an ARI. Main Outcomes and Measures The primary outcome was overall survival (OS), defined as time in months from mHSPC diagnosis to death or censoring at last recorded activity. Results Of 3404 patients (median [IQR] age, 73 [66-80] years), 1830 received treatment with an ASI (abiraterone), and 1574 with an ARI (507 apalutamide, 1067 enzalutamide). Following inverse probability of treatment weighting, patients receiving an ARI had significantly longer OS (median, 67.9 months [95% CI, 67.5 months to not reached]) compared with patients treated with the ASI (median, 57.2 months [95% CI, 52.7-63.3 months]) (hazard ratio [HR], 0.74 [95% CI, 0.64-0.87]); P < .001). Results were similar in sensitivity analyses using therapy initiation as the index date (HR, 0.73 [95% CI, 0.62-0.84]; P < .001) and when restricted to index dates on or after December 16, 2019 (HR, 0.67 [95% CI, 0.56-0.81]; P < .001). The association was not modified by insurance status or socioeconomic status. Conclusions and Relevance In this cohort study of 3404 patients with mHSPC, treatment intensification with an ARI was associated with significantly longer OS compared with an ASI. These findings may help guide clinical treatment selection and patient counseling. However, given conflicting clinical practice data across differing database populations, only a randomized clinical trial can definitively answer this question.