New data from the TALAPRO-2 trial reveals that combining talazoparib (Talzenna) with enzalutamide (Xtandi) significantly boosts overall survival in patients with metastatic castration-resistant prostate cancer (mCRPC). Presented at the 2025 Genitourinary Cancers Symposium, these findings promise a major advancement in the treatment of this aggressive form of cancer.
Enhanced Survival Benefits Clearly Demonstrated
The trial showed that the combination therapy extended median overall survival (OS) by 8.8 months, improving patient survival from 37.0 to 45.8 months. This translates to a 20.4% reduction in the risk of death.
Specifically, patients with homologous recombination repair (HRR)-deficient tumors saw even greater benefits, with a 38% reduction in death risk, and a median OS enhancement of 14 months. The hazard ratio for OS with talazoparib plus enzalutamide was 0.796 (95% CI, 0.661-0.958), indicating a statistically significant improvement.
Broader Impact Beyond HRR-Deficient Patients
The benefit extended beyond HRR-deficient patients. Those without DNA repair mutations also witnessed an OS gain of about 9 months, highlighting the versatility and widespread applicability of this therapy.
“TALAPRO-2 is groundbreaking, showing not only statistical but also clinically meaningful survival improvements in unselected and HRR-deficient mCRPC patients,” stated Neeraj Agarwal, MD, FASCO, professor of medicine at the University of Utah.
Detailed Subgroup Analysis Reveals Consistent Benefits
Among patients with no alterations detected by both circulating tumor DNA and tumor tissue, the median OS was 48.4 months in the talazoparib plus enzalutamide group compared with 37.1 months in the placebo group, demonstrating a 74.9% hazard ratio (95% CI, 0.582-0.963).
For those with BRCA1/2 alterations, the survival benefit was particularly striking, with none reaching median OS in the combination therapy group, compared to 28.5 months with enzalutamide alone.
Radiographic Progression-Free Survival Improvements
In addition to OS data, the trial also showed substantial improvements in radiographic progression-free survival (rPFS). Patients on talazoparib plus enzalutamide had a median rPFS of 49.5 months, compared with 33.8 months for those on placebo.
In the HRR-deficient group, the median rPFS was 30.7 months with combination therapy versus 12.3 months with enzalutamide alone, highlighting a significant potential for extended disease control.
Safety Profile
The trial’s safety profile was reassuring, with an anemia discontinuation rate of 8.5% for the talazoparib plus enzalutamide group compared to 8.4% for the enzalutamide alone group.
Agarwal noted, “We are encouraged by the results and excited about the potential impact on patient outcomes, especially given the lack of additional safety signals.”
Background and Rationale of TALAPRO-2
The phase 3, double-blind, placebo-controlled TALAPRO-2 trial aimed to determine whether adding talazoparib to enzalutamide could provide longer-lasting disease control in HRR gene-mutated mCRPC patients.
The study enrolled 805 patients randomized to receive either talazoparib 0.5 mg with enzalutamide 160 mg daily or placebo with enzalutamide daily, with stratification based on HRR gene alteration status. About 20% of patients had HRR alterations, including BRCA1 and BRCA2 mutations, distributed evenly between treatment groups.
Implications for Future Treatments
These findings have already led to FDA approval for the talazoparib/enzalutamide combination in HRR gene-mutant mCRPC, based on earlier data showing a 55% reduction in disease progression risk.
The new OS data from TALAPRO-2 provide a compelling rationale for expanding the use of this combination therapy to a broader patient population, including those without specific HRR mutations.
Conclusion
The TALAPRO-2 trial offers a significant leap forward in the treatment of mCRPC, offering a combination therapy that improves overall survival and extends disease control for both selected and unselected patients.
With these promising results, the future of advanced prostate cancer treatment looks more hopeful. Patients and healthcare providers can expect this combination to become a standard of care, offering substantial benefits and a better quality of life for those battling this disease.
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