Clinical and genomic determinants of extraordinary response and resistance to androgen receptor pathway inhibitors in men with metastatic androgen pathway modulator sensitive (APMS) prostate cancer.

Identifying clinical and genomic predictors of response to androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPI) for metastatic androgen pathway modulator sensitive (APMS) prostate cancer is essential for improving therapeutic decision-making. Divergent outcomes are observed in practice, with some achieving exceptional responses (ER) while others experience early resistance or non-response (NR), the biologic basis of which remains unclear. A retrospective review was conducted of patients with APMS prescribed ADT/ARPI from 2015-2024. ER and NR were defined by upper ( > 53.36 months) and lower ( < 10.41 months) quartiles of progression-free survival (PFS). Objectives were to associate baseline genomic and clinical factors with ER/NR status, PFS, overall survival (OS) and PSA kinetics.. Among 3363 prescribed ADT/ARPI, 224 were treated for APMS, with 154 (69%) undergoing temporal molecular testing. Alteration of ≥1 tumor suppressor gene with or without proliferative gene co-alteration was associated with NR while no single alteration predicted achieving ER. ECOG < 1, lack of pain, low-volume disease, higher hemoglobin and albumin, and normal alkaline phosphatase were associated with improved PFS, OS, and PSA nadir <0.2 ng/mL at 12 months. Alterations in TP53 (HR 1.60 [95%CI 1.02-2.50], p = 0.039; HR 1.91 [95%CI 1.05-3.49], p = 0.035) and MYC (HR 2.01 [95%CI 1.03-3.91], p = 0.040; HR 3.81 [95%CI 1.81-7.99], p < 0.001) were associated with inferior PFS and OS, while BRCA2 (HR 2.12 [95%CI 1.02-4.42], p = 0.045) additionally associated with PFS, and RAD21 (HR 2.55 [95%CI 1.13-5.77], p = 0.024) with OS. On multivariable analysis, MYC gain associated with OS (HR 4.41 [95%CI 1.24-15.7], p = 0.022). Pathway-level analysis showed proliferative gene alterations were associated with failure to achieve PSA nadir <0.2 ng/mL at 12 months (HR 0.49 [95%CI 0.24, 0.98], p = 0.047). In this real-world APMS cohort, we identified pre-treatment clinical and genomic predictors of patient benefits and long-term survival with ADT/ARPI therapy.