Treatment for advanced prostate cancer has advanced significantly in the past decade, but metastatic castration-resistant prostate cancer (mCRPC) remains an incurable disease. Homologous recombination repair (HRR) gene alterations are particularly common in these patients and are associated with a more aggressive disease phenotype and poor prognosis. Poly(ADP-ribose) polymerase (PARP) inhibitors, such as talazoparib, are considered an effective strategy for treating tumors with HRR mutations by acting on DNA damage repair pathways. Enzalutamide, a next-generation androgen receptor (AR) pathway inhibitor, is a standard first-line treatment for mCRPC. TALAPRO-2 is a Phase 3 clinical trial designed to evaluate the efficacy and safety of combining a PARP inhibitor (talazoparib) with an AR inhibitor (enzalutamide) for patients with mCRPC.
Methodology
TALAPRO-2 is an international, randomized, double-blind, placebo-controlled, Phase 3 clinical trial conducted at over 200 centers in 26 countries.
- Patient Population: Eligible participants were adult men with asymptomatic or mildly symptomatic mCRPC who had not received previous life-prolonging systemic therapy for mCRPC. Patients were receiving ongoing androgen deprivation therapy.
- Grouping and Randomization: Patients were randomized 1:1 into two treatment groups:
- Experimental Group: Oral talazoparib 0.5 mg daily + oral enzalutamide 160 mg daily.
- Control Group: Oral placebo daily + oral enzalutamide 160 mg daily.
- Stratification: Randomization was stratified by HRR gene alteration status (HRR-deficient vs non-deficient/unknown) and previous treatment for castration-sensitive prostate cancer (yes vs no). The study included two cohorts: one for HRR-deficient patients and an overall cohort not selected for HRR gene alteration status.
- Primary Endpoint: Radiographic progression-free survival (rPFS) as assessed by a blinded independent central review (BICR).
- Key Secondary Endpoints: Overall survival (OS), and patient-reported outcomes (PROs) including time to definitive deterioration in global health status/quality of life (GHS/QoL) and time to deterioration in pain symptoms.
- Safety Assessment: Safety was assessed in patients who received at least one dose of a study drug.
Detailed Study Findings
1. Overall Cohort (Unselected for HRR gene alteration status)
- Patients: 805 patients were enrolled with a median follow-up of 52.5 months.
- Overall Survival (OS): The combination therapy group showed a significant improvement in OS compared to the control group (HR=0.80, 95% CI 0.66-0.96; p=0.016).
- Median OS was 45.8 months for the combination group vs. 37.0 months for the control group, an extension of almost 9 months.
- Subgroup Analysis: The benefit was more pronounced in HRR-deficient patients (HR=0.55) and less so in HRR-non-deficient/unknown patients (HR=0.88).
- Radiographic Progression-Free Survival (rPFS): The rPFS benefit for the combination therapy group was sustained (HR=0.67, 95% CI 0.55-0.81; p<0.0001).
- Median rPFS was 33.1 months for the combination group vs. 19.5 months for the control group.
- Safety: Safety was consistent with the known profile of talazoparib. The most common Grade 3 or higher adverse events in the combination group were anemia (49% vs 4%) and neutropenia (19% vs 1%).
2. HRR-Deficient Cohort
- Patients: 399 HRR-deficient patients were enrolled with a median follow-up of 44.2 months.
- Overall Survival (OS): The combination therapy group resulted in a statistically significant and clinically meaningful improvement in OS compared to the control group (HR=0.62, 95% CI 0.48-0.81; p=0.0005).
- Median OS was 45.1 months for the combination group vs. 31.1 months for the control group, an extension of 14 months.
- BRCA1/2 Mutation Subgroup: The benefit was even more significant in patients with BRCA1/2 mutations (HR=0.50). The median OS for the combination group was not reached, compared to 28.5 months for the control group. The 4-year OS rates were 53% vs 23%.
- Non-BRCA1/2 Mutation Subgroup: There was also a benefit in patients with non-BRCA1/2 mutations (HR=0.73), but it did not reach statistical significance (p=0.066).
- rPFS: rPFS was significantly improved (HR=0.47, 95% CI 0.36-0.61; p<0.0001).
- Median rPFS was 30.7 months for the combination group vs. 12.3 months for the control group.
- Safety: The most common Grade 3 or higher adverse events were anemia (43%) and neutropenia (20%), similar to the overall cohort.
3. Patient-Reported Outcomes (PROs)
- HRR-Deficient Cohort:
- Patients in the combination group had a significantly longer time to definitive deterioration of Global Health Status/Quality of Life (GHS/QoL) (median 27.1 months vs 19.3 months; HR=0.69; p=0.032).
- Time to definitive deterioration of urinary symptoms was also significantly longer (HR=0.56; p=0.022).
- Time to deterioration of pain symptoms showed a trend towards being longer but was not statistically significant (p=0.051).
- The mean change from baseline in GHS/QoL, functioning, and symptom scores did not reach the clinically meaningful threshold of ≥10 points.
- Overall Cohort:
- Patients in the combination group had a longer time to GHS/QoL deterioration (median 30.8 months vs 25.0 months; HR=0.78; p=0.038).
- Time to urinary symptom deterioration showed a trend toward being longer (p=0.11).
- There was no significant difference in time to deterioration of pain symptoms or mean pain scores.
- The mean change from baseline in GHS/QoL, functioning, and symptom scores did not reach the clinically meaningful threshold.
Commentary and Implications
These study results collectively provide strong support for talazoparib plus enzalutamide as a first-line treatment for mCRPC patients and reveal the following important implications:
- Significant Efficacy: The combination therapy has achieved a significant and clinically meaningful breakthrough in extending OS and rPFS for patients with mCRPC. Especially in HRR-deficient patients, where OS was extended by 14 months and rPFS by nearly 1.5 years, this combination could become the new standard of care for this group of patients.
- HRR Gene Alterations as a Key Biomarker: The HRR gene alteration status is a crucial factor in predicting treatment benefit. Although some OS improvement was observed in patients without HRR deficiency, the magnitude of benefit was significantly higher in HRR-deficient patients, especially those with BRCA1/2 mutations. This highlights the importance of HRR genetic testing at the time of mCRPC diagnosis to guide personalized treatment decisions.
- Quality of Life Benefit: The combination therapy not only prolonged patient survival but also significantly delayed the deterioration of global health status and quality of life in HRR-deficient patients. This indicates that efficacy is not at the expense of patient quality of life, providing crucial support for clinical decisions.
- Manageable Safety: Although the combination therapy led to a higher incidence of hematological toxicity (anemia, neutropenia), these adverse events are manageable and consistent with the known safety profile of talazoparib. This requires enhanced monitoring and management of blood parameters during treatment.
- Mechanism of Combination Therapy: The combination of a PARP inhibitor like talazoparib and an AR inhibitor like enzalutamide may produce synergistic effects by inhibiting different DNA repair and AR pathways, thus enhancing therapeutic efficacy. This mechanism provides a theoretical basis for exploring more combination therapies in the future.
Next Steps for Research
Despite the great success of the TALAPRO-2 trial, some questions remain for further investigation:
- Further Exploration of the Non-BRCA1/2 HRR Mutation Subgroup: Although a significant benefit was observed in all HRR-deficient patients, the trend of benefit in patients with non-BRCA1/2 HRR mutations did not reach statistical significance. Further research is needed to identify which specific gene mutations are more sensitive to PARP inhibitors.
- Optimal Treatment Sequence: This study was conducted as a first-line treatment for mCRPC. Future research could explore whether this combination therapy remains effective after patients have progressed, and the optimal sequence of using talazoparib or enzalutamide after other treatments.
- Biomarker Optimization: Beyond HRR gene alterations, other biomarkers need to be identified to more precisely predict which patients will benefit from this combination therapy, enabling more personalized treatment.
- Long-term Safety: Although the interim safety profile is manageable, longer follow-up data are needed to assess the long-term risks of the combination therapy, especially its impact on cardiovascular events and secondary malignancies.
References
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Fay AP, Fizazi K, Matsubara N, Azad AA, Saad F, De Giorgi U, Joung JY, Fong PCC, Jones RJ, Zschäbitz S, Oldenburg J, Shore ND, Dunshee C, Carles J, Cislo P, Chang J, Healy CG, Niyazov A, Agarwal N. First-line talazoparib plus enzalutamide versus placebo plus enzalutamide in men with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations: patient-reported outcomes from the randomised, double-blind, placebo-controlled, phase 3 TALAPRO-2 trial. Lancet Oncol. 2025 Apr;26(4):481-490. doi: 10.1016/S1470-2045(25)00031-2
