In TALAPRO-2, one of the largest studies conducted in patients with metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) gene alterations, the prospectively defined, alpha-controlled primary outcome in the combined HRR-deficient population showed that talazoparib plus enzalutamide resulted in a clinically meaningful and statistically significant 55% reduction in risk of progression or death versus placebo plus enzalutamide as first-line treatment. These results build on the previous subgroup analysis of the patients with HRR-deficient tumours in the all-comers cohort. Although overall survival (OS) data are immature and statistical significance was not reached, interim data favour this combination.
Other key secondary endpoints, including time to PSA progression, time to chemotherapy and time to progression or death on the first subsequent antineoplastic treatment, favoured the talazoparib group. The findings are reported by Prof. Karim Fizazi of the Institut Gustave Roussy, University of Paris-Saclay in Villejuif, France, Prof. Neeraj Agarwal of the Huntsman Cancer Institute, University of Utah in Salt Lake City, UT, US, and study colleagues on 4 December 2023 in the Nature Medicine.
Around a quarter of advanced prostate cancers have alterations in DNA damage response genes involved directly or indirectly in HRR, including BRCA1/BRCA2; these can sensitise tumours to treatment with PARP inhibitors. PARP inhibition as monotherapy is an established standard of care for those patients with late-stage prostate cancer.
Monotherapy with the PARP inhibitor talazoparib 1 mg per day showed durable antitumour activity and a favourable benefit–risk profile in patients with heavily pretreated mCRPC with HRR gene alterations in the phase II, TALAPRO-1 study. Preclinical evidence suggests interplay between the androgen receptor (AR), which largely drives the growth of prostate cancer cells, and PARP, providing a rationale for their co-inhibition.
TALAPRO-2 is a multinational phase III study evaluating talazoparib in combination with the AR inhibitor enzalutamide as a first-line treatment in patients with mCRPC. Upon an initial, non-randomised, open-label run-in study, patients were enrolled in two cohorts: unselected (cohort 1, all-comers cohort, recruited first) for alterations in DNA damage response genes directly or indirectly involved in HRR and selected (cohort 2) to ensure enrollment of patients with HRR-deficient tumours.
The first 805 patients, of whom 169 with and 636 without HRR gene alterations were enrolled as all-comers in cohort 1. Subsequently, an additional 230 patients selected for HRR gene alterations were recruited to complete the predefined enrollment for a combined HRR-deficient population, in total 399. All patients were prospectively tested for HRR gene alterations.
A recent analysis of the all-comers population in TALAPRO-2 revealed significant improvement in radiographic progression-free survival (rPFS) for talazoparib plus enzalutamide compared with enzalutamide as standard of care with hazard ratio (HR) of 0.63 (95% confidence interval [CI] 0.51 to 0.78; p < 0.0001). In the latest article published in the Nature Medicine, the study team reported results of the prespecified alpha-powered independent analysis for the combined HRR-deficient population from both cohorts in TALAPRO-2 study.
Patients were randomized in a 1:1 ratio to talazoparib or placebo, plus enzalutamide. The primary endpoint, rPFS, was met with median not reached at the time of the analysis for the talazoparib group versus 13.8 months for the placebo group (HR 0.45, 95% CI 0.33 to 0.61; p < 0.0001). Data for OS, a key secondary endpoint, are immature but favour talazoparib (HR 0.69, 95% CI 0.46 to 1.03; p = 0.07).
TALAPRO-2 was not enriched for patients with BRCA1/BRCA2 alterations, which were well balanced between the treatment groups. Talazoparib plus enzalutamide reduced risk of progression or death by 80% in the BRCA1/BRCA2 subgroup and by 32% in the non-BRCA1/BRCA2 subgroup.
Common adverse events in the talazoparib group were anaemia, fatigue, and neutropenia. The most common grade ≥3 adverse event in the talazoparib group was anaemia (41%), with a median time to onset of 3.3 months, and requiring dose modification of talazoparib according to the protocol; 36% of patients in the talazoparib group received a packed red blood cell transfusion. However, only 4% of patients in the talazoparib group discontinued talazoparib due to anaemia.
After a median follow-up for safety of 15.4 and 12.9 months for the talazoparib and placebo groups, no cases of myelodysplastic syndrome or acute myeloid leukaemia were reported. Venous embolic and thrombotic events were reported in 7 patients in the talazoparib group and 2 patients in the placebo group. There were 4 cases of pulmonary embolism in the talazoparib group and 2 cases in the placebo group. There were no treatment-related deaths.
The authors commented that the main limitations of this study are due to the rapidly changing treatment landscape for patients with mCRPC. However, the TALAPRO-2 study results support the use of talazoparib plus enzalutamide as a potential first-line treatment option for patients with mCRPC harbouring tumour HRR gene alterations.
This study was sponsored by Pfizer Inc. Astellas Pharma Inc. provided enzalutamide.
Reference
Fizazi K, Azad AA, Matsubara N, et al. First-line talazoparib with enzalutamide in HRR-deficient metastatic castration-resistant prostate cancer: the phase 3 TALAPRO-2 trial. Nature Medicine; Published 4 December 2023. DOI: https://doi.org/10.1038/s41591-023-02704-x
