Study: Combination treatment for metastatic castration-resistant prostate cancer may be especially effective for people with BRCA1 or BRCA2 mutations

RELEVANCE

Most relevant for: People with metastatic castration-resistant prostate cancer.

It may also be relevant for:

• people with prostate cancer
• people with castration-resistant prostate cancer
• people with a genetic mutation linked to cancer risk

Relevance: High

Strength of Science: High

Research Timeline: Post Approval

More rating details

What is this study about?

The TALAPRO2 study looked at combining the PARP inhibitor Talzenna (talazoparib) with the hormone therapy Xtandi (enzalutamide). Specifically, it assessed whether this combination treatment improves survival and delays progression among people with metastatic castration-resistant prostate cancer (mCRPC) who have a mutation in certain genes involved in a type of DNA repair process called homologous recombination repair (HRR).

This study enrolled mCRPC patients with tumor mutations in the following HRR genes: ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MRE11A, NBN, PALB2 and RAD51C. The study also included patients with MLH1 mutations, although MLH1 is typically not considered to be an HRR gene.

Why is this study important?

mCRPC is an aggressive, life-threatening type of cancer that is even more aggressive when it is HRR-deficient. For people with mCRPC, treatment options are limited since the cancer no longer responds to standard hormone treatments. About 25% of people with mCRPC have a mutation in an HRR gene.

This study focused on how well Talzenna works to treat mCRPC with a mutation in the HRR genes listed above (or MLH1). Mutations in BRCA2, ATM and CDK12 were the most common among the 399 participants.

Prior research showed that treatment with Talzenna plus Xtandi lengthened the time before cancer grew or worsened. In this follow-up study, researchers report that participants treated with Talzenna plus Xtandi lived longer than those receiving Xtandi only.

Study findings

Of the 399 participants, half were treated with Talzenna and the usual treatment, Xtandi. The other half were treated with a placebo and Xtandi.

This was a double-blind study. Participants were randomly assigned to a treatment group, and neither the patient nor their doctor knew which treatment they received. Tumor testing was done to identify HRR gene mutations. Genetic testing for inherited mutations was not performed, so it is unknown whether participants had an inherited mutation or only a tumor mutation.

Overall results         

After nearly four years, there were fewer deaths among people with an HRR gene mutation who were  treated with Talzenna and Xtandi

• Participants treated with Talzenna and Xtandi survived an average of 45 months from the start of treatment.
• Participants treated with placebo and Xtandi survived an average of 31 months from the start of treatment.
• Talzenna extends survival for people with mCRPC and HRR gene mutations by more than one year. This finding is similar to study results for the entire TALAPRO2 study population of 805 people, including those with and without HRR mutations.  

Talzenna benefits people with a BRCA1 or BRCA2 mutation more than people with a mutation in other HRR genes

On average, people with any HRR gene mutation who were treated with Talzenna survived longer than those who did not receive Talzenna. However, Talzenna was even more beneficial for people with a BRCA1 or BRCA2 mutation compared to those without a BRCA mutation. Participants with a BRCA1 or BRCA2 mutation who received Talzenna plus Xtandi were twice as likely to survive as those who received placebo plus Xtandi.

Side effects of Talzenna and Xtandi

Most patients in both groups had some side effects (99% with Talzenna + Xtandi; 97% placebo + Xtandi).

The most common side effects seen in both study groups were:

• low red cell, white cell or plasma cell counts (35-67%)
• fatigue (35%)
• back pain (24%)
• decreased appetite (23%)
• high blood pressure (22%)
• nausea (22%)
• falls (20%)

Severe side effects (adverse events grade 3 or more) were more common in patients treated with Talzenna plus Xtandi (76%) than Xtandi alone (44%). The most common severe side effect in patients treated with Talzenna was low red blood cell counts (anemia, 43%); most were treated with blood transfusions.    

Serious or life-threatening side effects occurred in 6% of those treated with Talzenna + Xtandi and 1% of those treated with placebo + Xtandi. Most were serious cardiovascular problems, including blood clots in veins or arteries.

Some participants stopped treatment temporarily (a dose interruption) to recover from a side effect. Most dose interruptions were due to:

• low red blood cell counts (anemia)
• low white blood cell counts (neutropenia)
• low plasma cell counts (thrombocytopenia)

Other participants reduced Talzenna doses due to anemia (45%) or neutropenia (16%).
Participants in both groups stopped treatment completely due to side effects that were experienced at similar rates (10-13%).

What does this mean for me?

If you have mCRPC, you may be treated with Talzenna.  If your tumor has an HRR gene mutation, particularly a BRCA1 or BRCA2 mutation, Talzenna + Xtandi may help you live longer. Prior research suggests that Talzenna may also benefit people with mCRPC who do not have HRR mutations.

Although this combination treatment improves survival and delays disease progression, it can cause side effects. If you are treated with Talzenna, you are likely to experience some side effects, some of which may be severe. Your blood cell counts may need to be monitored, and you may need to interrupt a dose or reduce treatment. Although rare, some people treated with Talzenna experience severe cardiovascular problems, including blood clots.

Overall results from the study show that adding Talzenna to Xtandi may be a helpful option for treating mCRPC.

Reference

1. Fizazi K, Azad AA, Matsubara N, et al. Talazoparib plus enzalutamide in men with HRR-deficient metastatic castration-resistant prostate cancer: final overall survival results from the randomised, placebo-controlled, phase 3 TALAPRO-2 trial. Lancet. 2025; 406(10502):461-474.
2. Agarwal N, Azad AA, Carles, J, et al. Talazoparib plus enzalutamide in men with metastatic castration-resistant prostate cancer: final overall survival results from the randomized, placebo-controlled, phase 3 TALAPRO-2 trial. Lancet. 2025 406(10502):447-460.

Disclosure: FORCE receives funding from industry sponsors, including companies that manufacture cancer drugs, tests and devices. All XRAYS articles are written independently of any sponsor and are reviewed by members of our Scientific Advisory Board prior to publication to assure scientific integrity.

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posted 9/30/25