Patients with castration-resistant metastatic prostate cancer with or without HRR gene alterations treated with a combination of talazoparib and enzalutamide may live longer compared to patients treated with enzalutamide alone. However, patients with HRR gene alterations may receive greater benefit compared to those without. This research was presented at the 2025 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium, taking place February 13-15 in San Francisco, California. 

Patients included in the study had asymptomatic or mildly symptomatic mCRPC and had not previously received treatment for castration-resistant disease. The study was divided into two cohorts, or groups. In cohort 1, patients were randomly assigned to receive either talazoparib and enzalutamide (402 patients) or placebo and enzalutamide (403 patients) regardless of HRR gene alteration status. This means that some participants had HRR gene alterations and some did not. Cohort 2 included only participants who had HRR gene alterations. Of the 399 patients in this cohort, 200 were randomly assigned to receive talazoparib and enzalutamide and 199 received a placebo and enzalutamide.

Patients who received talazoparib and enzalutamide had a median OS of 45.8 months. The median OS for patients who were treated with the placebo and enzalutamide was 37 months. 

After a median follow-up of 52.5 months, 211 patients who were treated with talazoparib and enzalutamide had died. In comparison, 243 patients who were treated with placebo and enzalutamide had died. Patients treated with talazoparib and enzalutamide had a 20% lower risk of dying than patients treated with placebo and enzalutamide.

Patients who were treated with talazoparib and enzalutamide also saw an improvement in progression-free survival (PFS), or time during which their cancer remains stable or regressed. The median PFS in the talazoparib and enzalutamide group was 33.1 months. In the placebo and enzalutamide group, the median PFS was 19.5 months.

Within cohort 1, researchers also looked at subgroups of patients to understand the benefit of this treatment combination. Out of all the patients: 

• There were 169 patients with cancers that were HRR-deficient, which is a specific type of HRR alteration. When these patients took the talazoparib and enzalutamide combination, they had a 45% lower risk of dying. 
• The remaining 636 patients with cancers that were not HRR-deficient or cancers with unknown HRR statuses had a 12% lower risk of dying when they took the talazoparib and enzalutamide combination. 

Some of the patients in this cohort had results from both circulating tumour DNA (ctDNA) and tissue samples. Out of these, researchers looked at two subgroups: 

• There were 439 patients with cancers that did not have BRCA1/BRCA2 mutations. When these patients took the talazoparib and enzalutamide combination, they had a 25% lower risk of dying.
• There were 314 patients with cancers that did not have any HRR alterations (stringently tested by both tumor tissue and the ctDNA testing). When these patients took the talazoparib and enzalutamide combination, they had a 22% lower risk of dying with a 9-month improvement in overall survival with the combination of talazoparib and enzalutamide 

In cohort 2 the median OS for patients who were treated with talazoparib and enzalutamide was 45.1 months, while the median OS for patients treated with placebo was 31.1 months.

Patients treated with talazoparib and enzalutamide had a 38% lower risk of death than those treated with placebo and enzalutamide.

The median PFS was 30.7 months for patients treated with talazoparib and enzalutamide and the median PFS was 12.3 months for patients treated with a placebo and enzalutamide.

A total of 26 patients (13%) stopped treatment with talazoparib because of side effects. 

The most common severe side effects were anaemia and neutropenia with 86 patients (22%) stopping treatment with talazoparib because of side effects.

Researchers will continue to study how the talazoparib and enzalutamide combination works to treat patients with mCRPC who were previously treated with docetaxel, a chemotherapy drug, and/or an ARPI drug. They are also studying this combination in patients with metastatic castration-sensitive prostate cancer. 

“The TALAPRO-2 study showed a significant improvement in overall survival in men with mCRPC treated with the combination of talazoparib and enzalutamide whether they had HRR gene alterations. In this sub-analysis, men without HRR-deficient or cancers with unknown HRR statuses had modest clinical benefit. Careful consideration of the risk and benefits of talazoparib and enzalutamide should be given in the treatment of patients with mCRPC that do not have HRR gene alterations or unknown HRR status,” said William Kevin Kelly, DO, Thomas Jefferson University Hospital.

“TALAPRO-2 is the first trial to show a clinically meaningful and statistically significant improvement in overall survival in patients with mCRPC when the combination of a PARP inhibitor plus an androgen receptor pathway inhibitor was compared with the standard-of-care ARPI enzalutamide in mCRPC regardless of whether or not they had HRR gene alterations. These findings represent the longest median OS and the largest improvement in median OS observed among randomized, controlled phase 3 trial in mCRPC ​ conducted to date,” said lead study author Neeraj Agarwal, MD, FASCO, Huntsman Cancer Institute in Salt Lake City, UT.

Source: ASCO