Androgen Receptor T878A and L702H Alterations Define Subsets of Prostate Cancer Patients with Distinct Outcomes to Androgen Receptor Pathway Inhibitors

Metastatic androgen pathway modulation-resistant (mAPMR) prostate cancer subtypes harboring androgen receptor (AR) alterations have distinct AR biology that may impact response to therapy. We hypothesized that patients harboring AR T878A would have superior responses to AR pathway inhibitor (ARPI) therapy based on prior preclinical data. We utilized a large genomic-clinical database to identify mAPMR patients with AR T878A, AR L702H and AR amplification and performed a matched assessment of ARPI treatment outcomes using real-world surrogate endpoints for treatment response. Among AR T878A patients treated with enzalutamide, time to treatment discontinuation (TTD) was longer relative to patients with AR L702H (8 mo (95% CI 4.6–44 mo) vs. 3.5 mo (95% CI 2.3–5.5 mo) log-rank p < 0.0001) or AR amplification (7.7 mo (95% CI 4.7–15.8 mo) vs. 4.8 mo (95% CI 4–5.1 mo) (log-rank p = 0.0034). Among the AR T878A patients treated with abiraterone, TTD was not significantly different relative to patients with AR L702H, but longer relative to patients with AR amplification (7.1 mo (95% CI 5–8.5 mo) vs. 4.2 mo (95% CI 3.5–5.4 mo) (log-rank p = 0.037). This study provides hypothesis generating evidence that outcomes for patients with AR LBD mutations may differ by mutation subtype. AR T878A may be relatively more sensitive to ARPI treatment than AR L702H or amplified AR.