FDA Approves Talzenna Plus Xtandi for Earlier-Stage Metastatic Prostate Cancer With DNA-Repair Gene Mutations

Men whose prostate cancer has spread but still responds to hormone therapy have a new option if their tumors carry certain DNA-repair mutations. The Food and Drug Administration on Monday approved Pfizer’s Talzenna (talazoparib) in combination with Xtandi (enzalutamide) for that group, moving the two-pill regimen into an earlier stage of the disease.

The approval covers adults with metastatic prostate cancer that has not yet been treated with, or is still responding to, drugs that block the androgen pathway, and whose tumors have mutations in homologous recombination repair (HRR) genes, according to the FDA. Doctors usually call this metastatic hormone-sensitive or castration-sensitive prostate cancer. Patients must be identified with an FDA-authorized test.

Until now, the combination was approved in the United States only for men with HRR-mutated cancer that had stopped responding to standard hormone therapy, a later and harder-to-treat stage known as castration-resistant prostate cancer.

What did the TALAPRO-3 trial show?

The FDA based its decision on TALAPRO-3, a randomized, double-blind phase 3 trial of 599 men with HRR-mutated metastatic hormone-sensitive prostate cancer. Half took Xtandi with Talzenna and half took Xtandi with a placebo. Everyone also stayed on standard androgen deprivation therapy, which lowers testosterone. The study is listed on ClinicalTrials.gov as NCT04821622.

The main goal was radiographic progression-free survival, the time until scans showed the cancer growing or the patient died. Men on the placebo combination went a median of 45.8 months before that happened. In the Talzenna group, the median had not yet been reached when the data were analyzed, meaning more than half of those patients were still free of progression.

Overall, adding Talzenna lowered the risk of the cancer progressing or death by 52% compared with Xtandi alone. The benefit held in men with BRCA mutations, where the risk dropped by about 63%, and in men with other HRR mutations, where it fell by about 43%, according to results reported by CancerNetwork.

Survival data were still immature at the time of the analysis. An interim look showed a trend toward longer overall survival that did not reach statistical significance. The results were presented at this year’s American Society of Clinical Oncology annual meeting and published in The New England Journal of Medicine.

Who is eligible for the new approval?

The label applies to men whose tumors carry a mutation in one of 12 HRR genes, including BRCA1, BRCA2, ATM, CHEK2, CDK12 and PALB2. These genes help cells repair damaged DNA. When they are broken, cancer cells lean on a backup repair system run by an enzyme called PARP. Talzenna is a PARP inhibitor, so it shuts down that backup, while Xtandi blocks the hormone signals that fuel prostate tumors.

The FDA has already cleared two Foundation Medicine tests as companion diagnostics for the combination: FoundationOne CDx, which uses a tumor tissue sample, and FoundationOne Liquid CDx, which uses a blood sample. That makes genetic testing a practical first step for men newly diagnosed with metastatic disease.

The recommended dose of Talzenna is 0.5 milligrams by mouth once a day alongside Xtandi. Men taking the combination also need ongoing hormone therapy with a GnRH analog unless they have had both testicles surgically removed.

What did Pfizer and doctors say?

When the FDA accepted the application for priority review in July, Pfizer chief oncology officer Jeff Legos said treating men at the hormone-sensitive stage “represents an important opportunity to delay progression before the disease becomes more difficult to manage.” He added that the trial data “reinforce the importance of biomarker testing to inform treatment decisions as early as possible.”

Dr. Neal Shore, medical director of the Carolina Urologic Research Center and the trial’s lead investigator, told CancerNetwork that the progression-free survival curves for the two groups “separate very early, within a matter of a few months,” calling that “remarkably impactful.”

The review moved through Project Orbis, an FDA program that lets cancer regulators in several countries review the same application at the same time. Australia’s Therapeutic Goods Administration and Health Canada took part, and their reviews are ongoing. Pfizer markets Xtandi with Astellas.

What are the side effects and risks?

The prescribing information carries warnings for myelodysplastic syndrome and acute myeloid leukemia, two blood cancers that have been seen with PARP inhibitors. It also warns about myelosuppression, a drop in red cells, white cells and platelets, and about harm to a developing fetus.

In practice, that means regular blood tests during treatment. Patients should tell their care team about unusual tiredness, easy bruising or bleeding, fever, or frequent infections. Men with partners who could become pregnant should ask about birth control during treatment and after the last dose.

What does this mean for patients?

Prostate cancer is the most common cancer in American men after skin cancer, and most men whose disease has spread start on hormone therapy. This approval gives oncologists a reason to check for HRR mutations at diagnosis rather than waiting until the cancer becomes resistant.

Men with metastatic prostate cancer who have not had genetic testing of their tumor or blood can ask their oncologist whether it makes sense now. It is the latest in a busy fall for cancer treatment news, which has included the FDA’s decision on Jemperli for some rectal cancer patients and late-stage data on a personalized mRNA melanoma vaccine.

Key Takeaways

• The FDA on Oct. 26 approved Talzenna plus Xtandi for HRR-mutated metastatic prostate cancer that is still hormone-sensitive, an earlier stage than its previous approval.
• In the 599-patient TALAPRO-3 trial, the combination cut the risk of cancer progression or death by 52% compared with Xtandi alone.
• Patients must have an HRR gene mutation found by an FDA-authorized tissue or blood test.
• Overall survival data are not yet mature. Warnings include blood cancers, low blood counts and harm to a fetus.

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