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:
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.2 has previously established the efficacy of combination therapy of a PARP-inhibitor with abiraterone acetate in this same population of men.
- 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
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 first phase of the trial (P1) is an open-label study to confirm the starting dose of TALA to be given in combination with ENZA. Phase 2 (P2) is a randomized double-blind study that will evaluate the safety, efficacy and patient-reported outcomes of TALA (0.5 mg QD) + ENZA (160 mg QD) vs placebo + ENZA in 2 cohorts (C).
Cohort 1 (C1): Patients with mCRPC (all comers) – expected recruitment N = 560
Cohort 2 (C2): Patients with DDR gene mutations likely to sensitize to PARP inhibition (DDR deficient) – expected recruitment N = 300.
The full trial design is below:
Randomization will be stratified by prior treatment with NHT for castration sensitive prostate cancer (CSPC) or prior treatment with taxane-based chemotherapy for CSPC (yes/no), and DDR mutation status (deficient vs. nondeficient/unknown).
In terms of outcomes, for the first phase, the primary endpoint is safety and the secondary endpoint is pharmacokinetics of TALA and ENZA. For phase 2, the primary endpoint is radiographic progression-free survival (rPFS), defined as time to progression in soft tissue per RECIST v1.1 or in bone per PCWG3 criteria or death and evaluated separately in all comers (C1) and DDR-deficient (DDR-deficient pts from C1 and C2 combined, N = 380 pts) populations. The key secondary endpoint is overall survival.
Study endpoints are summarized below:
Efficacy and progression will be assessed by radiographic evaluation every 8 weeks up to week 25 and every 8-12 weeks thereafter. Phase 2 analysis for rPFS is powered at 90% and 85% using a 2-sided log-rank test with alpha of 0.025, respectively, in the all comers and DDR deficient populations.
Estimated dates: Last patient visit September 2022, Study Completion November 2024
This study was sponsored by Pfizer Inc. Further Clinical trial information can be found online. Clinical Trial information: NCT03395197
Presented by: Neeraj Agarwal, MD, is an Associate Professor in the Division of Oncology
Co-Authors: Neal D. Shore, Curtis Dunshee, Lawrence Ivan Karsh, Beth Sullivan, Nicola Di Santo, Mohamed Elmeliegy, Michelle Casey, Ruben G.W. Quek, Akos Czibere, Karim Fizazi
Written by: Thenappan Chandrasekar, MD (Clinical Instructor, Thomas Jefferson University) (twitter: @tchandra_uromd, @JEFFUrology) at the 2019 American Society of Clinical Oncology Genitourinary Cancers Symposium, (ASCO GU) #GU19, February 14-16, 2019 - San Francisco, CA
- 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.
- 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.