The androgen axis remains active, even in patients with advanced and castration-resistant prostate cancer. As a result, androgen axis targeting agents, including abiraterone and enzalutamide have proven beneficial in this disease space. There is a rationale for the combination of PARP inhibitors and androgen axis inhibition because PARP activity supports androgen receptor function. Thus, inhibition of PARP activity would be expected to decrease androgen receptor signaling and increase the efficacy of agents targeting the androgen axis. Further, androgen receptor blockade downregulated transcription of genes involved in DDR which induces a “DDR mutant-like state” even in patients without germline or somatic DDR mutations.
Building on this concept, in a Poster Session at the 2020 American Society of Clinical Oncology Virtual Annual Meeting, Neeraj Agarwal, MD, and colleagues present the design and rationale of phase III TALAPRO-2 trial which randomizes patients with metastatic castration-resistant prostate cancer to a PARP inhibitor, talazoparib, and enzalutamide or enzalutamide alone while assessing efficacy, safety, pharmacokinetics, and patient-reported outcomes (PROs). Talazoparib is one of many PARPi available on the market. It has been approved in many countries as monotherapy for patients with human epidermal growth factor receptor 2-negative advanced breast cancer who have known DDR mutations (BRCA1 and BRCA2).
Patients could not have received novel androgen axis inhibiting agents (e.g. abiraterone, enzalutamide, or apalutamide) at the time of castration-sensitive prostate cancer (mCSPC), though they could have received cytotoxic chemotherapy. Further, they could not have received life-prolonging therapy at the time of nonmetastatic CRPC or mCRPC. Patients had to continue on ADT (either via surgical castration or ongoing LHRH agonist or antagonist) throughout the study. Additional exclusion criteria included a lack of adequate organ function.
The TALAPRO-2 study will recruit adult men (age 18 years or greater) with metastatic castration-resistant prostate cancer who have asymptomatic or minimally symptomatic disease. Patients had to have progressive disease at study entry defined by at least one of the following: PSA progression, soft-tissue progression, or bony disease progression. Further, patients have to have an ECOG performance status of 0 or 1 and a life expectancy of at least 12 months.
The first portion of the study was an open-label, non-randomized dose-finding study. This was performed among 19 patients. Based on part 1, part 2 of the trial involves a randomized, double-blind, placebo-controlled trial of talazoparib (0.5mg daily) and enzalutamide (160mg daily) versus placebo and enzalutamide. Randomization was stratified according to receipt of prior novel hormonal therapy or docetaxel for CSPC (yes or no) and DDR alteration status (deficient vs nondeficient/unknown) with a primary outcome of radiographic progression-free survival (rPFS), defined as time to progression in soft tissue per RECIST v.1.1 or bone per PCWG3 criteria by independent review or death and key secondary outcome of overall survival.
The total enrollment goal is 1037 patients: 19 patients, part 1 dose-finding; 1,018 patients, part 2 placebo-controlled.
Presented by: Neeraj Agarwal, MD, Profesor of medicine, an investigator at the Huntsman Cancer Institute (HCI), University of Utah, Salt Lake City, Utah
Co-Authors: Neal D. Shore, Curtis Dunshee, Lawrence Ivan Karsh, Arun Azad, Andre P. Fay, Joan Carles, M. Luisa Paccagnella, Nicola Di Santo, Mohamed Elmeliegy, Xun Lin, Ruben G.W. Quek, Akos Czibere, Karim Fizazi
Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center, Twitter: @WallisCJD at the 2020 America Society for Clinical Oncology Virtual Annual Meeting (#ASCO20), May 29th-31st, 2020