TALAPRO-2 Overall Survival Data Suggest New Standard of Care in mCRPC, Regardless of Genomic Status

A therapeutic combination previously approved for men with genetic-mutated advanced prostate cancer could become standard of care for all patients with this disease, regardless of their genomic status, based on data presented Thursday at the American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU) in San Francisco, California.

Final data from TALAPRO-2 (NCT03395197), a phase 3 trial of talazoparib (Talzenna; Pfizer) and enzalutamide (Xtandi; Astellas/Pfizer) in men with metastatic castration-resistant prostate cancer (mCRPC) showed the combination reduced the risk of death 20.4% in patients whether or not they had homologous recombination repair (HRR) gene alterations.

Neeraj Agarwal, MD, FASCO | Image credit: LinkedIn

Data from this larger group of patients in the study, called the unselected cohort because they were enrolled regardless of their genomic status, were presented at the opening session by global lead investigator Neeraj Agarwal, MD, FASCO, of Huntsman Cancer Institute, University of Utah. Agrawal said the trial offered the first meaningful survival benefit from 2 key drug classes in prostate cancer—a poly ADP-ribose polymerase (PARP) inhibitor; and an androgen receptor pathway inhibitor (ARPI).

HRR deficiency affects 20% to 30% of men with mCRPC, and over the past decade its presence had indicated the potential use of PARP inhibitors, of which talazoparib is a newer-generation example. Enzalutamide, meanwhile, is an androgen receptor pathway inhibitor (ARPI) that interrupts the AR signaling process at several points.

“In the real world, overall survival for patients with metastatic castration resistant prostate cancer, or mCRPC, is less than 3 years, and nearly half of these patients receive only 1 systemic therapy,” Agrawal said. He showed a diagram that demonstrated how simultaneously inhibiting PARP and ARPI may work together to have an effect greater than the sum of these mechanisms working separately, “and may extend to those patients with mCRPC who do not have HRR alterations.”

Discussant Tanya B. Dorff, MD, of City of Hope Comprehensive Cancer Center, noted that some of colleagues in the field have questioned this synergy, but she points to a mCRPC study by Maha Hussain, MD, the BRCAaway trial, which found that the combination of abitarone and olaparib worked better in combination and was well tolerated than the therapies in sequence.

“Obviously, more data are needed, but this really does suggest there is synergy. Importantly, we don't see synergy in terms of toxicity. We did not see any safety signals when combining these classes of drugs, compared to using them alone,” she said.

Tanya B. Dorff, MD | Image credit: City of Hope

In an interview with The American Journal of Managed Care®, Dorff elaborated on the way talazoparib and enzalutamide interact effectively against cancer without increased toxicity.

Often, she said, “When we put 2 drugs together, we get more than the typical toxicity that you see with 1 drug or the other. But in this case, the side effect profile was essentially exactly the same, at least in TALAPRO-2,” compared to using talazoparib alone or enzalutamide alone. This is good news, given the length of time patients must take the combination, Dorff said.

Dose reductions may occur due to anemia, but these occur with or without a combination regimen, she said.

Two Cohorts in Study

Agrawal presented data from Cohort 1, the unselected group, which randomized 805 patients who enrolled in the trial regardless of genomic status. After 52.5 months of follow-up, the median OS was 45.8 months for the patients receiving the combination and 37.0 months for those receiving enzalutamide plus placebo. The hazard ratio (HR) for patients receiving the combination compared with those receiving enzalutamide only was 0.796 (95% CI, 0.661-0.958; 2-sided P = .0155).1

Agrawal noted that the benefits of the combination were seen across subgroups, and in an exploratory analysis. There were no new safety signals, and treatment-emergent adverse events (AEs) were generally manageable A total of 86 patients stopped taking talazoparib due to AEs.

Cohort 2 involved 399 patients whose tumors had known HRR alterations. These results were presented in a separate late-breaking poster by Karim Fizazi, MD, PhD, a professor at Institut Gustave Roussy, University of Paris-Saclay.2 After 44.2 months, the median OS for this cohort was 45.1 months in the combination group vs 31.1 months in the enzalutamide-only group, (HR, 0.62; 95% CI, 0.48-0.81; P = .0005), for a 38% reduction in the risk of death. An exploratory analysis showed that OS benefits were seen in patients with BCRA alterations and other alterations.

“Wisely, the investigators chose not to ignore genomics, and the patients with homogolous recombination repair alteration are clearly going to derive benefit in a different way than patients without an alteration,” Dorff explained during the session.

For the TALAPRO-2 combination, it’s been a matter of waiting for the data. In June 2023, the combination of talazoparib and enzalutamide received FDA approval based on radiographic progression-free survival (rPFS) data for patients with HRR deficiencies.3 OS data were not mature. In October, Pfizer announced that the OS data for TALAPRO-2 were positive.

In a statement, Pfizer’s Chief Oncology Officer Roger Dansey, MD, said the company looked forward to working with regulatory officials on label updates to reflect these new data.

“Survival rates in metastatic castration-resistant prostate cancer are poor due to the advanced and aggressive stage of the disease. Today’s results demonstrate the potential for [this combination] to be a practice-changing treatment to help improve patient survival in mCRPC,” Agrawal said in a statement from Pfizer.

References

1. Agrawal N, Azad A, Charles J, et al.Final overall survival with talazoparib + enzalutamide as first-line treatment in unselected patients with metastatic castration-resistant prostate cancer in the phase 3 TALAPRO-2 trial. J Clin Oncol. 2025;43(suppl 5): Abstract LBA18. doi: 10.1200/JCO.2025.43.5_suppl.LBA18

2. Fizazi K, Azad A, Matsubara N. Final overall survival with talazoparib + enzalutamide as first-line treatment in patients with homologous recombination repair-deficient metastatic castration-resistant prostate cancer in the Phase 3 TALAPRO-2 trial. J Clin Oncol. 2025;43(suppl 5): Abstract: LBA141 doi: 10.1200/JCO.2025.43.5_suppl.LBA141

3. Agarwal N, Azad AA, Carles J, et al. Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial. Lancet. 2023;402(10398):291-303.