ASCO 2019: Clinical and Safety Outcomes of TALAPRO-2: A Two-part Phase III Study of Talazoparib in Combination with Enzalutamide in Metastatic Castration-resistant Prostate Cancer

Chicago, IL (UroToday.com) Enzalutamide is an androgen-axis targeted therapy with established efficacy in the treatment of advanced prostate cancer (PCa), including metastatic castration-resistant PCa (mCRPC) and non-metastatic CRPC (nmCRPC).

TALA is a poly(ADP-ribose) polymerase (PARP) inhibitor that inhibits PARP1/PARP2 and traps PARP on DNA, preventing DNA damage repair (DDR), and causing cell death in BRCA1/2-mutated cells. TALA is approved in the US to treat germline BRCA1/2-mutated HER2- locally advanced/metastatic breast cancer. It has a dual cytotoxic mechanism highlight below:
ASCO 2019 dual cytoxic mechanisms
Prior studies have demonstrated the potential benefit of PARP inhibitors in the treatment of advanced prostate cancer, particularly in men with DNA repair defects.1 Indeed, work by Clarke et al previously established the efficacy of combination therapy of a PARP-inhibitor with abiraterone acetate in this same population of men.2
  • AR signaling inhibition suppresses the expression of genes associated with DNA damage repair
  • PARP1 activity has been shown to support AR function, suggesting that co-blockade may synergize with AR-directed therapy
In this study, Neeraj Agarwal, MD, and colleagues examine the combination of TALA with ENZA in mCRPC, with the expectations that it may improve clinical outcomes, based on the strength of prior studies.

Eligibility criteria for both parts of the trial are as follows:
  • Men aged ≥18 years
  • Have asymptomatic/mildly symptomatic mCRPC
  • ECOG PS ≤1
  • No brain metastases
  • Have not received taxanes/novel hormonal therapy (NHT)
The study design is as follows:
ASCO 2019 TALA ENZA study design

This is a 2-part trial, with Part 1 (12 patients minimum) designed to determine TALA starting dose based on safety and pharmacokinetics (PK) evaluation of TALA + ENZA. Part 2 is the 1:1 blinded randomization of an expected 860 patients.

In this poster session, they report clinical and safety outcomes, specifically from part 1 of the study.

The starting dose of TALA in the first 13 patients was 1 mg once daily (QD) + ENZA 160 mg QD (1 mg QD cohort). But, based on the safety review of pre-specified target safety events and pharmacokinetics data, TALA dose was reduced to 0.5 mg QD. Subsequent patients were treated with a starting dose of TALA 0.5 mg QD + ENZA 160 mg QD (0.5 mg QD cohort).

To date, 19 patients were enrolled in part 1 of the study (1 mg QD cohort: 13; 0.5 mg QD cohort: 6). The median (range) age was 71 yrs (52-82). The remainder of the demographics were not provided at this time.

As of the analysis cutoff date, the median treatment duration was 25 and 11 weeks for the 1 mg QD and 0.5 mg QD cohorts, respectively. Treatment-emergent adverse events (TEAEs) occurred in 19 pts. The full results are below:

ASCO 2019 treatment emergent adverse events

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 4 pts (30.8%) and 3 pts (50%) 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.

In terms of early results, 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. This is seen below:

ASCO 2019 PSA reduction from baseline

Pharmacokinetic 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. This was likely due to P-gp/BCRP inhibition by enza and its metabolite. By week 13, once enza metabolism had stabilized, so did tala exposure.

Based on this safety and pharmacokinetics data from part 1 of the TALAPRO-2 study, it appears that the reduced dose of TALA 0.5 mg QD + ENZA 160 mg QD has a manageable safety profile in patients with mCRPC and will be the starting dose for the randomized part 2 portion of TALAPRO-2.

Presented by: Neeraj Agarwal, MD, Associate Professor, Division of Oncology, Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah

Written by: Thenappan Chandrasekar, MD (Clinical Instructor, Thomas Jefferson University) (twitter: @tchandra_uromd, @JEFFUrology) at the 2019 ASCO Annual Meeting #ASCO19, May 31- June 4, 2019, Chicago, IL USA

References:
  1. Mateo N, et al. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. N Engl J Med. 2015 Oct 29;373(18):1697-708. doi: 10.1056/NEJMoa1506859.
  2. Clarke N, Wiechno P, Alekseev B, Sala N, Jones R, Kocak I, Chiuri VE, Jassem J, Fléchon A, Redfern C, Goessl C, Burgents J, Kozarski R, Hodgson D, Learoyd M, Saad F. Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2018 Jul;19(7):975-986. doi: 10.1016/S1470-2045(18)30365-6. Epub 2018 Jun 4.
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