Adrenal androgens and overall survival (OS) in men with castration-resistant prostate cancer (CRPC) treated with enzalutamide without (ENZ) or with abiraterone and prednisone (ENZ/AAP) (Alliance).

230 Background: DHEA, testosterone (T) and androstenedione (AD) are adrenal androgens that can drive CRPC. HSD3B1 encodes for 3β-hydroxysteroid dehydrogenase-1 (3βHSD1) and has 2 common missense-encoding germline variants: the more active adrenal-permissive allele and the less active adrenal-restrictive allele that are associated with greater and lesser non-gonadal androgen biosynthesis from DHEA. A single adrenal-permissive HSD3B1 (1245C) allele is sufficient to confer more rapid development of CRPC and homozygous inheritance (about 7-10% of men) is the most common monogenic link to prostate cancer mortality. Alliance A031201 (NCT01949337) is a phase 3 trial of ENZ versus ENZ/AAP for metastatic CRPC. This analysis combines clinical outcomes associated with adrenal androgens and HSD3B1 as the gene encoding the enzyme that uses dehydroepiandrosterone (DHEA). Methods: Germline DNA was genotyped for HSD3B1 in 929 men from A031201 (469 ENZ and 460 ENZ/AAP). Baseline DHEA, T and AD were assessed in 922 men (464 ENZ and 458 ENZ/AAP) using mass spectrometry. The Cox proportional hazards model was used to determine the prognostic significance of DHEA, T and AD categorized as tertiles in predicting OS. Results: In the combined treatment arms, median (95% CI) OS for men in low, medium and high DHEA tertiles was 27 (25, 31), 36 (33, 42) and 39 (37, 47) months (Table). In the ENZ arm, men with inheritance of 0, 1 and 2 adrenal-permissive alleles had median OS of 34 (30, 39), 34 (29, 39) and 28 (23, 37) months. Conclusions: DHEA is the most informative adrenal androgen. Men with the lowest tertile for this substrate of 3βHSD1 have the shortest OS. These data are consistent with prior analyses demonstrating poor prognosis for men with low adrenal androgens. Outcomes for men homozygous for the adrenal-permissive HSD3B1 allele treated with ENZ are consistent with prior retrospective studies. Overall survival and adrenal androgens. Serum Androgen Median OS in months (95% CI) Multivariable Hazard Ratio (95% CI) DHEA 1 st Tertile (Low) DHEA 2 nd Tertile (Medium) DHEA 3 rd Tertile (High) 27 (25, 31)36 (33, 42)39 (37, 47) AC vs. AA 0.97 (0.82,1.14)CC vs. AA 1.08 (0.81,1.44)DHEA: Med vs High 1.17 (0.97,1.42)DHEA: Low vs. High 1.65 (1.37,2.00) AD 1 st Tertile (Low) AD 2 nd Tertile (Medium) AD 3 rd Tertile (High) 32 (27, 36)36 (34,43)34 (31, 39) AC vs. AA 0.96 (0.82,1.13)CC vs. AA 1.08 (0.81, 1.44)AD: Med. vs. High 0.89 (0.73,1.07)AD: Low vs. High 1.16 (0.97,1.40) T 1 st Tertile (Low) T 2 nd Terile (Medium) T 3 rd Tertile (High) 28 (26, 35)37 (34, 41)36 (32, 41) AC vs. AA 0.95 (0.81,1.12)CC vs. AA 1.07(0.80,1.43)T: Med vs. High 1.01 (0.83,1.22)T: Low vs. High 1.28 (1.06,1.54)