Introduction & Objectives: TALA, a dual-mechanism poly(ADP-ribose) polymerase (PARP) inhibitor, inhibits PARP catalytic activity and traps PARP on DNA. ENZA is a novel hormonal therapy approved for 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 breast cancer resistance protein (BCRP). Prior to initiation of TALAPRO-2 (NCT03395197) Part 1, the in vivo effect of ENZA on exposure of P-gp and BCRP substrates (eg, TALA) had not been evaluated. TALAPRO-2 Part 1 determined TALA starting dose based on safety and pharmacokinetic (PK) evaluation of TALA+ENZA.
Materials & Methods: Patients (pts) ≥18 y of age had European Cooperative Oncology Group performance status ≤1 and no prior systemic treatment for mCRPC. Starting dose of TALA (first 13 pts) was 1 mg once daily (QD) + ENZA 160 mg QD (1 mg QD cohort). Based on a review of prespecified target safety events and PK data, TALA was reduced to 0.5 mg QD; additional pts received a starting dose of TALA 0.5 mg QD + ENZA 160 mg QD (0.5 mg QD cohort).
Results: 19 pts enrolled in Part 1 (1 mg QD cohort, n=13; 0.5 mg QD cohort, n=6). Median (range) age was 71 y (52-82). At analysis cut-off date, median treatment duration was 25 and 11 wks for 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 prostate-specific antigen in the 1 mg QD and 0.5 mg QD cohorts, respectively, demonstrating preliminary anti‑tumor activity. PK data showed ENZA increased TALA exposure; TALA 0.5 mg QD + ENZA maintained similar TALA exposure to 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.
© 2019 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2019 ASCO Annual Meeting. All rights reserved.
Funding: Sponsored by Pfizer Inc.; Astellas Pharma Inc. provided enzalutamide.
