ASCO GU 2023: TALAPRO-2: Phase 3 Study of Talazoparib + Enzalutamide Versus Placebo + ENZA as First-Line Treatment in Patients with mCRPC

( TALAPRO-2 is a phase III study evaluating the combination of the poly (ADP-ribose) polymerase inhibitor talazoparib and enzalutamide versus enzalutamide and placebo as first-line treatment in patients with metastatic castration-resistant prostate cancer (mCRPC). It exists in the landscape of sequential and advancing studies of PARP inhibitors (PARPi) in prostate cancer. There are two key characteristics that distinguish TALAPRO-2 from other PARPi studies. These are the inclusion of a genomically-unselected (“all comers”) group (cohort 1) as well as a DNA damage response (DDR) mutated group (cohort 2). Secondly, this is truly a first line CRPC study with no other therapies allowed in castration resistance prior to enrolling on TALAPRO-2. Prior chemotherapy was allowed in metastatic castration sensitive disease, but no prior AR pathway inhibitor (ARPI) was permitted in any setting.

Dr. Neeraj Agarwal shares data on behalf of the study team. He began by briefly reminding the audience of the rationale for simultaneously inhibiting PARP and AR signaling, noting that there is bidirectional effects: PARPi can suppress AR transcriptional activity and ARSIs can disrupt repair of singly stranded breaks. Additional study background include eligibility criteria of prior progression (PSA, soft tissue via RECIST, or bony via PCWG3), minimal or absent symptoms, and performance status via ECOG of 0-1. HR gene testing was used as a prospective stratification factor with 99.9% of patients with tissue for testing.


Primary endpoint of the study was radiographic PFS via RECIST in those patients with evaluable soft tissue and in bones via PCWG3, in both cohorts. Secondary endpoints include overall response (OS), duration of response, PSA response of ≥90%, time to PSA progression, time to cytotoxic chemotherapy, and time to antineoplastic therapy, PFS2 (PFS on the therapy that follows this study), and patient-reported outcomes (PROs).

Baseline demographics and disease characteristics of the study were well-balanced between treatment arms, with a highlight made of the rates of known mutations in HR mediating genes of 21.1% and 20.8%, respectively, in experimental and control arms.


At median follow up of nearly 25 months in both arms, the primary end point of rPFS via blinded independent review demonstrated a 37% risk of progression or death in the patients receiving talazoparib and enzalutamide, with 151 events in the experimental and 191 events in the control arm. Median rPFS was not yet reached with addition of talazoparib as compared to 21.9 months (95% CI 16.6-25.1). The HR for rPFS was 0.63 (0.51-0.78) with p<0.001. The benefit was consistently reported in investigator-reported data as well.


Critically, the rPFS when examined separately for HRR mutated and HRR unmutated (or unknown) were presented. The benefit of talazoparib was present in groups, with a larger one, as anticipated, in those patients harboring known alteration in HRR-mediating genes (27.9 v 16.4 months, HR 0.46 [0.30-70], p<0.001).


Specifically, when limited to those patients with known absence of mutation in target genes, to exclude the possibility of patients in the “unknown” group harboring relevant occult mutations, the benefit of talazoparib persisted as follows.


Objective response rates via BICR showed higher ORR and complete response rates in the experimental arm with an impressive CR rate of 37.5% (vs 18.2%) .


Treatment emergent adverse events (TEAEs) demonstrated high rates of cytopenias in the experimental arm. In fact the most common TEAEs resulting in dose reduction of talazoparib were anemia (43.2%), neutropenia (15.1%), and thrombocytopenia (5.5%). It was highlighted that 49% of patient entered the study with baseline grade 1 or 2 anemia. The onset of grade 3-4 anemia occurred at a median time of 3.3 months. Only 8.3% of patients discontinued talazoparib due to anemia and the dose reductions were needed. Despite dose reductions, the median relative dose intensity was ≥80% (0.4 mg/daily).

Overall survival data were reported but were not mature or yet suggestive of significance. However, patient-reported global health status per EORTC QLQ-C30 showed a statistically significant improvement in time to clinically-meaningful deterioration of quality of life.


Dr. Agarwal concludes that all patients in the study benefited from the addition of talazoparib to enzalutamide in first line mCRPC. Although the benefit appears strongest in patients with mutations in HR mediating genes, those patients with negative testing still could experience significant benefit in rPFS versus enzalutamide alone. Anemia appears well-managed with dose adjustments. As OS data are pending and the debate about the appropriateness of rPFS as a surrogate for OS, the QOL data are compelling that the patient experience on the combination may be improved.

Presented by: Neeraj Agarwal, MD, FASCO, Huntsman Cancer Institute, University of Utah (NCI-CCC)

Written by: Jones Nauseef, MD, PhD, Assistant Professor of Medicine within the Division of Hematology and Medical Oncology, Sandra and Edward Meyer Cancer Center, and Englander Institute for Precision Medicine Weill Cornell Medicine and Assistant Attending physician at NewYork-Presbyterian Hospital. @DrJonesNauseef on Twitter during the 2023 Genitourinary (GU) American Society of Clinical Oncology (ASCO) Annual Meeting, San Francisco, Thurs, Feb 16 – Sat, Feb 18, 2023. 

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