ESMO 2021: TALAPRO-3: A Phase 3, Double-blind, Randomized Study of Enzalutamide Plus Talazoparib versus Placebo Plus Enzalutamide in Patients with DDR Gene Mutated Metastatic Castration-sensitive Prostate Cancer

(UroToday.com) The European Society of Medical Oncology (ESMO) 2021 annual meeting’s prostate cancer session included a presentation by Dr. Neeraj Agarwal discussing the TALAPRO-3 trial concept and design, a phase 3 trial assessing enzalutamide plus talazoparib versus placebo plus enzalutamide in men with DDR gene mutated metastatic castration-sensitive prostate cancer. Treatment for metastatic castration-sensitive prostate cancer (mCSPC) should be individualized to the patient, but one standard-of-care therapy involves androgen deprivation therapy (ADT) in combination with an androgen axis inhibitor, such as enzalutamide. Talazoparib is a poly (ADP-ribose) polymerase (PARP) inhibitor approved as monotherapy for germline BRCA1/2-mutated HER2- negative advanced breast cancer. PARP inhibitors have demonstrated substantial clinical efficacy in homologous recombination repair (HRR)/DNA damage response (DDR)-altered metastatic castration-resistant prostate cancers (mCRPC).

Previously, phase III study results in the PROfound trial led to the approval of olaparib for mCRPC.¹ Enzalutamide is an androgen receptor inhibitor and established therapy for mCSPC. As PARP activity has been shown to support androgen function, PARP inhibition is expected to increase sensitivity to androgen receptor-directed therapies. In addition, androgen receptor blockade downregulates HRR gene regulation, which has been hypothesized to induce a “BRCAness” phenotype. A Phase II study of talazoparib monotherapy (TALAPRO-1) demonstrated robust antitumor activity in men with heavily pretreated, HRR-mutated mCRPC.² The phase III, double-blind, randomized trial TALAPRO-3 (NCT04821622) will compare the combination of talazoparib plus enzalutamide versus placebo plus enzalutamide in men with mCSPC with DDR/HRR alterations.

Approximately 550 pts with mCSPC harboring DDR/HRR alterations will be randomized to talazoparib (0.5 mg once daily) plus enzalutamide (160 mg once daily) or placebo (once daily) plus enzalutamide (160 mg once daily). It is anticipated that enrollment will be approximately 25 participants per month for an accrual duration of ~22 months. A total of 158 radiographic progression-free survival events will provide ~80% power to detect a target hazard ratio of 0.63, using a 2-sided log-rank test with a 5% significance level. As follows is the study design for the TALAPRO-3 study:

Key eligibility criteria are:

Age ≥18 years
Histological diagnosis of prostate cancer
Alterations in 12 DDR/HRR genes known to sensitize to PARP inhibitors (ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C)
Metastatic disease (no brain metastases)

The primary endpoint is radiographic progression-free survival (time to radiographic progression in soft tissue per RECIST v.1.1 or in bone per PCWG3 criteria by investigator, or death). Secondary endpoints include overall survival, safety, and patient-reported outcomes, with a full list of endpoints as follows:

Patient recruitment is planned at 285 sites, in 28 countries, including the US, Europe, South America, South Africa, and Asia-Pacific:

Presented by: Neeraj Agarwal, MD, Clinical Research Innovation, University of Utah Health - Huntsman Cancer Institute, Salt Lake City, UT

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2021 European Society for Medical Oncology (ESMO) Annual Congress 2021, Thursday, Sep 16, 2021 – Tuesday, Sep 21, 2021.

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