Profiling of exceptional responders (ER) and non-responders (NR) to androgen receptor pathway inhibitors (ARPI) in men with metastatic hormone sensitive and castration resistant prostate cancer.

e17107 Background: In clinical practicea subset of patients treated with androgen deprivation therapy (ADT) plus an ARPI achieve prolonged benefit (ER) while some patients experience early resistance (NR), in both metastatic hormone-sensitive (HSPC) and castrate-resistant (CRPC) settings. We evaluated baseline clinical and genetic features of patients achieving real-world ER or NR ARPI outcomes. Methods: A physician-abstracted chart review of Duke Health patients prescribed ARPI from 2015-2024 determined duration of clinical benefit (DoCB; ARPI start to discontinuation for progression or next therapy). ER and NR were defined by upper (>35mo HSPC, >29mo CRPC) and lower (<11.3mo HSPC, <8.5mo CRPC) quartiles of DoCB. Temporal molecular testing was defined as tissue or blood cfDNA testing prior to ARPI start or within 3mo if NR or 6mo if ER. The primary objective was to associate baseline molecular profiles and clinical factors with ER vs NR status. Results: Of 3,363 prescribed an ARPI, 749 (22%) had tumor molecular data registered; of these, 111 had temporal molecular testing (77% Foundation CDX of tumor tissue) and also met upper quartiles for ER (n=53; 64% HSPC, 36% CRPC) or lower quartiles for NR (n=58; 48% HSPC, 52% CRPC). Expectedly, median OS (NR vs 19mo in HSPC and NR vs 12mo in CRPC) and PFS (NR vs 6mo in HSPC and 37mo vs 3.3mo in CRPC) was longer for ER vs NR patients. Clinical and genetic factors associated with ER are shown in Table 1. Consistent clinical predictors of ER in both disease states included functional status, disease volume, pain, anemia, and albumin levels. Adjusting for a 10% false discovery rate, in HSPC we found that lack of TP53 or any tumor suppressor (TSG; TP53, RB1, PTEN), lack of MYC gain, and APC mutations were associated with ER to ARPI therapy. In mCRPC, lack of TP53 or TSG loss, or AR alterations (OR 6.7 [95%CI 1.1-100]) predicted ER, with a trend for SPOP predicting ER (OR 6.2 [0.7-132]). On multivariate analysis of the HSPC cohort, ECOG 0, lack of liver metastases or anemia, and lack of TP53 alteration independently associated with ER. Conclusions: In this real-world selected cohort of exceptional responders and non-responders to ARPI, we identified critical pre-treatment clinical and genetic predictors of patient benefits and long-term survival. Factors associated with exceptional response to ARPI therapy. mHSPCOdds Ratio (95%CI) mCRPCOdds Ratio (95%CI) ECOG 0 vs 1-3 6.8 [2.08-27] 7.9 [2.09-35.5] Lack of pain 5.8 [1.97-18] 16.4 [3.5-121] Low volume disease 4.1 [1.32-14.5] 6.7 [1.8-28] Lack of anemia 1.77 [1.31-2.58] 2.79 [1.57-6.07] Normal albumin 5.73 [1.49-28.8] 24.8 [2.93-401] Lack of TP53 alteration 2.8 [0.99-8.1] 4.8 [1.38-19] APC mutation 7.0 [1.1-136] 0.87 [0.11-5.01] Lack of MYC amplification 7.2 [1.07-142] N/A No tumor suppressor losses (TP53/RB1/PTEN) 2.6 [0.93-7.7] 7.1 [2.04-33]