Clinical and safety outcomes of TALAPRO-2: A two-part phase III study of talazoparib (TALA) in combination with enzalutamide (ENZA) in metastatic castration-resistant prostate cancer (mCRPC).

Abstract

5076 Background: TALA is a dual-mechanism PARP inhibitor that inhibits PARP catalytic activity and traps PARP on DNA. ENZA is a novel hormonal therapy approved to treat castration resistant prostate cancer. TALA + ENZA may improve clinical outcomes for men with mCRPC. However, TALA, is a substrate for efflux drug transporters P-gp and BCRP. Prior to the initiation of TALAPRO-2 part 1, the in vivo effect of ENZA on exposure of P-gp and BCRP substrates, such as TALA, had not been evaluated. Methods: TALAPRO-2 part 1 was designed to determine TALA starting dose based on safety and pharmacokinetics (PK) evaluation of TALA + ENZA. Pts were ≥18 yrs of age, had ECOG PS ≤1, with no prior systemic treatment for mCRPC. The starting dose of TALA in the first 13 pts was 1 mg once daily (QD) + ENZA 160 mg QD (1 mg QD cohort). Based on safety review of prespecified target safety events and PK data, TALA dose was reduced to 0.5 mg QD; additional pts were treated with a starting dose of TALA 0.5 mg QD + ENZA 160 mg QD (0.5 mg QD cohort). Results: 19 pts were enrolled in part 1 (1 mg QD cohort, 13; 0.5 mg QD cohort, 6). The median (range) age was 71 yrs (52-82). As of the analysis cutoff date, the median treatment duration was 25 and 11 wks for the 1 mg QD and 0.5 mg QD cohorts, respectively. Treatment-emergent adverse events (TEAEs) occurred in 19 pts. The most common TEAE, anemia, occurred in 76.9% and 33.3% of pts in the 1 mg QD and 0.5 mg QD cohorts, respectively. TEAEs that led to TALA dose reduction occurred in 6 pts (46.2%) and 0 pts in the 1 mg QD and 0.5 mg QD cohorts, respectively. In the 1 mg QD cohort, target safety events were reported for 7 pts (53.8%) vs 0 in the 0.5 mg QD cohort. 92% and 100% of pts had a 50% decline from baseline in PSA in the 1 mg QD and 0.5 mg cohorts, respectively, demonstrating preliminary anti-tumor activity. PK data showed that ENZA increased TALA exposure and that TALA 0.5 mg QD + ENZA maintained similar TALA exposure to that achieved with 1 mg QD monotherapy. Conclusions: TALA 0.5 mg QD + ENZA 160 mg QD had a manageable safety profile in pts with mCRPC and will be the starting dose for the randomized portion of TALAPRO-2. Clinical trial information: NCT03395197.