Regulatory Pfizer's Talzenna gets wider approval for prostate cancer compared...

Pfizer’s Talzenna gets wider approval for prostate cancer compared to AstraZeneca and Merck


Pfizer’s Talzenna has received FDA approval as a second PARP inhibitor for prostate cancer, marking a significant development within a short timeframe. Although the approval is broader than the first inhibitor, it does come with certain limitations. Talzenna, in combination with Xtandi, has been authorized by the FDA to treat metastatic castration-resistant prostate cancer (mCRPC) in patients with specific gene mutations known as homologous recombination repair (HRR) gene mutations.

This approval for Talzenna comes just three weeks after AstraZeneca and Merck’s Lynparza received approval for front-line mCRPC treatment when used in combination with Johnson & Johnson’s Zytiga. However, Lynparza’s approval is limited to patients with tumors carrying BRCA mutations, which is a subset of HRR mutations.

Pfizer estimates that HRR gene mutations account for approximately 25% of mCRPC cases, while BRCA mutations make up around 10% of the entire mCRPC population. Consequently, Talzenna’s approval encompasses a larger proportion of patients compared to Lynparza.

Currently, Talzenna has the most extensive label among PARP inhibitors for mCRPC in the United States. Johnson & Johnson is seeking FDA approval for a combination of niraparib (marketed as Zejula by GSK outside of prostate cancer) and Zytiga, but their application is limited to patients with BRCA-mutant disease.

Pfizer is optimistic that longer-term data can support an even broader indication for Talzenna in mCRPC, regardless of the genetic mutation status. The FDA has approached the review of PARP inhibitors cautiously, requesting drug manufacturers to limit existing approvals for ovarian cancer due to concerns about the balance between efficacy and risks in cancers without BRCA or HRR mutations.

The FDA’s approval of Talzenna was based on results from the phase 3 TALAPRO-2 trial. In cohort 1, which included patients with or without HRR mutations, the addition of Talzenna to Xtandi demonstrated a 37% reduction in the risk of tumor progression or death, as presented at the American Society of Clinical Oncology Genitourinary Cancers Symposium in February.

It is important to note that the approved indication for Talzenna only covers patients with HRR mutations. However, when data from HRR-mutant patients in cohort 1 and a separate cohort consisting solely of HRR-mutant patients were combined, there was a 55% improvement in progression-free survival when Talzenna was combined with Xtandi, compared to Xtandi alone.

Previously, the FDA granted approval for Lynparza but restricted it to patients with BRCA mutations. The FDA’s analysis of the phase 3 PROpel trial raised concerns about the drug’s impact on patient survival in those without BRCA mutations, despite its demonstrated benefit in delaying tumor progression. Additionally, a design flaw in the trial created uncertainties regarding Lynparza’s effectiveness in other HRR alterations.

While Talzenna has shown promising survival data for the overall trial population, the survival results are still premature, and the FDA requires more data before approving a label covering the non-HRR subgroup. The overall survival (OS) data is expected to mature in 2024, and if the combination therapy demonstrates a benefit in OS, Pfizer intends to seek potential approval for its use in all patients, irrespective of genetic mutation status.

In the meantime, Talzenna has presented positive data in patients with non-BRCA HRR mutations, which has instilled enough confidence in the FDA to grant the current approval. In this subgroup, the combination of Talzenna and Xtandi has shown a 28% improvement in progression-free survival and a 29% reduction in the risk of death.

Pfizer and Astellas are also conducting trials to evaluate Talzenna in combination with Xtandi for HRR-mutated metastatic hormone-sensitive prostate cancer, with an expected completion date in late 2024. These studies aim to further expand the potential use of Talzenna in the treatment of prostate cancer.

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