Treatment and outcomes among patients with metastatic castrate resistant prostate cancer with an AR gene alteration: Analysis from the Kaiser Permanente Northern California Healthcare System.

91 Background: Androgen gene alterations (mutAR) are a key mechanism of resistance in metastatic castrate-resistant prostate cancer (mCRPC) and are most frequently found after exposure to Novel Hormonal Agents (NHA). Optimal treatment for patients with mCRPC and androgen receptor mutations is evolving. Current NCCN guidelines recommend continued androgen deprivation therapy (ADT) in mCRPC, with sequential use of novel hormone agents (NHA), or non-NHA therapies such as taxane-based chemotherapy, PARP inhibitors, immunotherapy, and Lutetium 177–PSMA-617 for appropriately selected patients. We sought to evaluate the benefit of therapy in patients with mutAR in a real-world setting. Methods: Between November 2017 and July 2025, 2193 patients in the Kaiser Permanente Northern California (KPNC) health system with advanced prostate cancer had tumor specimens examined by next generation sequencing (NGS). Of these patients, we retrospectively identified 67 mCRPC patients with mutAR. Patient records were reviewed to determine baseline demographic characteristics, therapies for Castrate Sensitive Prostate Ca (CSPC), and mCRPC characterized as NHA and non-NHA therapies, progression free survival (PFS), and overall survival (OS). The primary outcome was PFS on 1st and 2nd therapy for CRPC. Secondary outcomes were OS and PFS for NHA based therapy compared to non-NHA based therapy. Results: Median age for the 67 patients with mCRPC and mutAR was 72.4 years (Range 44-93). Forty-seven (70%) were non-Hispanic white; 8 (12%) were African American; and 6 (9%) were Asian. AR amplification was the most frequent alteration (74.6%). AR H875 was the most frequent ligand-binding domain mutation (11.9%). TP53 (52.2%), PTEN (34.3%) and CCND1 (13.4%) were the most common co-mutated genes. Median PFS was 11 months for 1 st line therapy and 4.5 months for 2 nd line therapy following diagnosis of CRPC based on Prostate Cancer Working Group criteria. Among the 67 patients with mCRPC with mutAR, 51 patients received ADT plus NHA, and 16 patients received ADT plus non-NHA therapy in the 1 st line setting. Median PFS was 13 months for ADT plus NHA and 5 months for ADT plus non-NHA therapy. Median PFS in the 2 nd line setting was 5 months for ADT plus NHA and 4 months for ADT plus non-NHA therapy. Median OS for the cohort was 34 months (95% CI 23.8-49 months). Median OS was 43.4 months for patients with ADT plus NHA and 20.7 months for the patients with ADT plus non-NHA therapy. Conclusions: In this real-world study within KPNC, we found that AR amplification was the most common AR gene alteration. In the 1st line CRPC setting, PFS was longer for patients receiving NHA vs non-NHA therapies. Better therapies are needed for subsequent line therapy.