Among patients with metastatic castration-resistant prostate cancer (mCRPC), new final overall survival (OS) data from the TALAPRO-2 trial confirm that the combination of Talzenna (talazoparib) plus Xtandi (enzalutamide) provides a significant survival benefit, according to findings presented at the 2025 Genitourinary Cancers Symposium.
The trial demonstrated an 8.8-month improvement in median OS, with the combination therapy extending survival to 45.8 months compared with 37 months with Xtandi alone, representing a 20.4% reduction in the risk of death.
Patients with homologous recombination repair (HRR)-deficient tumors had an even greater 38% reduction in the risk of death, translating to a 14-month OS improvement. In this group, the median OS with Talzenna plus Xtandi was 45.1 months and 31.1 months in the placebo and Xtandi arm. However, the benefit extended beyond patients who were HRR-deficient, as those without DNA repair mutations also saw an OS gain of approximately nine months.
“TALAPRO-2 is the first PARP inhibitor plus [androgen receptor pathway inhibitor (ARPI)] combination study to show not only a statistically significant, but also a clinically meaningful improvement in overall survival in patients with metastatic CRPC in unselected and in HRR-deficient [patients],” Dr. Neeraj Agarwal, FASCO, professor of medicine, Presidential Endowed Chair of Cancer Research, director, the Genitourinary Oncology Program, the Center of Investigational Therapeutics, the Huntsman Cancer Institute (HCI), University of Utah.
Glossary:
ECOG performance status of 1 or lower: patients are fully active (0) or restricted in strenuous activity but ambulatory and able to perform light work (1).
Overall survival (OS): time from treatment initiation to death from any cause.
Metastasis: spread of cancer from the primary site to distant organs.
Castration-resistant: prostate cancer that progresses despite androgen deprivation therapy.
HRR-deficient: tumors with homologous recombination repair gene mutations, affecting DNA repair.
PARP inhibitor plus androgen receptor pathway inhibitor (ARPI): combination therapy targeting DNA repair and androgen signaling in prostate cancer.
Radiographic progression-free survival (rPFS): time until radiographic disease progression or death.
Looking at OS in subgroups of patients with no alterations detected by both circulating tumor DNA and tumor tissue, those with no BRCA alterations detected had a median OS of 48.4 months in the Talzenna and Xtandi arm and 37.1 months in the placebo and Xtandi arm. For those with no HRR alterations detected, the median OS in the Talzenna plus Xtandi arm was 46.6 months and 37.4 months for those given placebo and Xtandi.
In patients with BRCA1/2 alterations, the median OS was not reached in the Talzenna plus Xtandi arm versus 28.5 months in the placebo plus Xtandi arm. For those with non-BRCA1/2 HRR alterations, the median OS was 42.4 versus 32.6 months.
The trial’s primary end point, radiographic progression-free survival (rPFS), also saw a substantial improvement. Patients receiving Talzenna plus Xtandi had a median rPFS of 33.1 months, compared with 19.5 months with Xtandi alone.
In the HRR-deficient cohort, patients given Talzenna plus Xtandi had a median rPFS of 30.7 months, compared with 12.3 months with Xtandi alone.
For safety, there were no new safety signals seen after an additional two years of follow-up in either patient population. While grade 3 (severe) or 4 (life-threatening) anemia was the most common side effect, occurring in 49% of patients in the unselected population and 43.4% in the HRR-deficient population, it was largely manageable with dose adjustments. Patients also reported that their quality of life was maintained, even with the extended treatment duration.
In the unselected patient population, the rate of discontinuation due to side effects was 21.6%, which was similar to that seen in the primary analysis, and 8.5% of patients discontinued Talzenna treatment due to anemia. In the HRR-deficient population, the rate of discontinuation of Talzenna due to side effects was 13.1% and 4.5% of patients discontinued treatment due to anemia.
Overall, these data support the broad use of this combination in both HRR-deficient and non-deficient populations.
“We are very encouraged, very happy with these results and also there were no safety signals seen. So, we really hope this combination makes a difference in our patients lives,” added Agarwal.
Background and Rationale of TALAPRO-2
The phase 3, double-blind, placebo-controlled TALAPRO-2 trial was designed to test whether combining the PARP inhibitor Talzenna with Xtandi could provide longer-lasting disease control and improve survival outcomes in patients with HRR gene-mutated mCRPC compared with placebo plus Xtandi.
Male patients aged 18 and older were eligible to enroll in the study if they had progressive disease at study entry, an ECOG performance status of 1 or lower, and a life expectancy of at least 12 months. Those who had been previously treated with a second-generation ARPI, PARP inhibitor, cyclophosphamide or mitoxantrone for prostate cancer; clinically significant cardiovascular disease; or significant renal or hepatic dysfunction were ineligible for participation.
A total of 805 patients were randomly assigned in cohort 1 to receive Talzenna 0.5 milligrams (mg) with Xtandi 160 mg per day (402 patients) or placebo and Xtandi 160 mg per day (403 patients). Randomization was stratified by HRR gene alteration status. The study’s primary end point was rPFS.
One hundred percent of patients underwent prospective tumor tissue testing before enrollment. In this cohort, 20% of patients were found to have HRR alterations. For specific gene alterations, BRCA1, BRCA2, ATM and CDK12 mutations were evenly distributed between the treatment arms. Notably, BRCA1 and BRCA2 alterations were present in approximately 7% of patients.
In June 2023, the Xtandi combination for the treatment of HRR gene-mutant mCRPC, supported by data from TALAPRO-2. The data the FDA considered at the time showed that the combination led to a 55% reduction in the risk of disease progression or death. The median rPFS at the time was not reached with Talzenna and Xtandi versus 21.9 months with placebo plus Xtandi.
References:
“Final overall survival (OS) with talazoparib (TALA) + enzalutamide (ENZA) as first-line (1L) treatment in patients (pts) with homologous recombination repair (HRR)-deficient metastatic castration-resistant prostate cancer (mCRPC) in the phase 3 TALAPRO-2 trial.” By Dr. Karim Fizazi, et al. J Clin Oncol.
“Final overall survival (OS) with talazoparib (TALA) + enzalutamide (ENZA) as first-line treatment in unselected patients with metastatic castration-resistant prostate cancer (mCRPC) in the phase 3 TALAPRO-2 trial,” by Dr. Neeraj Agarwal et al. J Clin Oncol.
“Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial,” by Dr. Neeraj Agarwal, et al. Lancet.
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