Racial differences in organic anion transport proteins (OATP) and outcome in castration resistant prostate cancer treated with AR pathway inhibitors in Alliance A031201: A phase III trial.

Abstract

246 Background: Serum androgen levels are prognostic in mCRPC and genetic variation in androgen metabolism may drive these effects. OATPs, encoded by genes of the solute carrier organic anion (SLCO) family, govern the uptake of steroids. We hypothesize variation in androgen uptake may drive differential outcomes on ARPI therapy. A secondary analysis was the contribution of race to prevalence and outcome with the variants. Methods: A031201 was a randomized phase 3 trial in progressive mCRPC by Prostate Cancer Working Group 2 (PCWG2) criteria. Patients (pts) were randomized 1:1 to enzalutamide (ENZ) or ENZ plus abiraterone (AAP) at standard doses. Castrating therapy was maintained. The primary endpoint was overall survival (OS). Secondary endpoint was radiographic-free survival (rPFS). Germline DNA was genotyped for SLCO2B1 in 772 men from A031201 using a validated melting assay. 458 ENZ/AAP). Race is self-reported. Proportional hazards model was used to determine if variants predict OS/rPFS. Results: Two SLCO2B1 variants were analyzed (rs12422149 – GG (82% prevalence) vs AA allele (2% prevalence), and rs1789693 AA (prevalence 43%) vs TT allele (prevalence 13%). 105 (11%) Black patients were genotyped for rs1789693, prevalence of AA was 9%, with median rPFS 67 mos, OS of 67 mos; 50% had TT, median rPFS 16 mos (HR = 3.25 (95% CI 1.16-9.12) OS was 23 mos (hazard ratio for death 2.60 95% CI1.01-6.68). Hazard ratios for homo and heterozygotes are shown (Table). Conclusions: In black men, variations in OATP may contribute to differences in outcome when treated with ARPI therapy. Further study of these interactions with other factors is warranted. Clinical trial information: NCT01949337 . Outcome by genotype. Genotype Median in Months (95% CI) Hazard Ratio (95% CI) SLCO2B1_rs1789693 OS Black (n = 102)AA 67 (52, -) (n = 9)AT 36 (27, 53) (n = 42)TT 23 (20,42) (n = 51) Referent (ref)AT vs. AA 2.02 (0.78,5.26)TT vs. AA 2.60 (1.01, 6.68) White (n = 772; 5 undetermined (und))AA 35 (32-37) (n = 322)AT 36 (22, 39) (n = 346)TT 31 (27,43) (n = 99) RefAT vs. AA 1.01 (0.85,1.21)TT vs. AA 0.99(0.75-1.30) rPFS Black (n = 102)AA 67 (31, NR) (n = 9)AT 23 (17, 39) (n = 42)TT 16 (13,26) (n = 51) RefAT vs. AA 2.84 (1.00,8.07)TT vs. AA 3.25 (1.16, 9.12) White (n = 772; 5 und)AA 23 (20, 27) (n = 322)AT 23 (20, 25) (n = 346)TT 26 (17, 34) (n = 99) RefAT vs. AA 1.02 (0.86,1.21)TT vs. AA 0.85 (0.65, 1.12) SLCO2B1_rs12422149 OS Black (n = 102; 1 und)GG 36 (26,52) (n = 74)AG 26 (21, NR) (n = 27)AA NR (n = 0) RefAG vs GG 0.96 (0.56, 1.66)AA vs GG NE White (n = 772; 3 und)GG 34 (32,37) (n = 630)AG 36 (32, 44) (n = 125)AA 42 (25,NR) (n = 14) RefAG vs. GG 0.91 (0.72, 1.66)AA vs. GG 0.70 (0.35-1.41) rPFS Black (n = 102; 1 und)GG 23 (17,39) (n = 74)AG 20 (13, NR) (n = 27)AA NR (n = 0) RefAG vs GG 1.04 (0.61, 1.78) AA vs GG NE White (n = 772; 3 und)GG 23 (20,25) (n = 630)AG 22 (18, 26) (n = 125)AA 34 (14,NR) (n = 14) RefAG vs GG 1.07 (0.86, 1.3) AA vs. GG 0.63 (0.32,1.27) NR=not reached; NE= Not estimable.