Good afternoon, I am Dr. Amanda Berhaupt, the Health Policy Director at the National Center for Health Research. We are a nonprofit think tank that evaluates scientific evidence on the safety and efficacy of drugs, biologics, and medical devices. We do not accept funding from entities with a financial interest in our work, so we have no conflicts of interest. I am a proud FDA alumna and appreciate the chance to share NCHR’s concerns about the TALAPRO-2 trial at this important meeting.
In 2023, the FDA approved an indication for Talzenna in combination with Xtandi for patients with metastatic castration-resistant prostate cancer (mCRPC) with an HRR mutation. Patients in the TALAPRO-2 trial who received Talzenna + Xtandi reported a better quality of life for longer than Xtandi alone. We applaud this progress for the indicated use that benefits patients’ well-being.
An article from the National Cancer Institute in 2023 with study authors urged patients who receive this diagnosis should get genetic testing to identify inherited mutations ‘for drugs that can target the specific alterations that drive someone’s tumor, and for screening for germline alterations in families.’
We are here today to discuss the potential expansion of indication for use in patients without an HRR mutation, representing the majority of patients with metastatic castration-resistant prostate cancer (mCRPC).
As you know, there were two cohorts in the TALAPRO-2 trial:
- Cohort 1 or the “all-comers” included everyone regardless of genetic mutation.
- And Cohort 2 enrolled only patients with a positive result with a genetic mutation.
We agree with the FDA’s viewpoint that the study design of the trial demonstrates flaws that complicate parsing results to understand if and how this drug combination provided the same benefits identified for those with an HRR mutation.
As we’ve heard, Overall Survival improved for all-comers in Cohort 1. However, some patients in Cohort 1 did not know their HRRm status and subsequent testing indicated that many within this cohort had the mutation.
Only 7% of patients with a HRRm tumor and 9% with BRCAm tumor received subsequent PARPi in the control arm. This likely influenced the difference observed in Overall Survival.
Currently, PARPi are approved only for patients with those tumor mutations. Trials of other PARPi have not supported an all-comers indication. So, we agree with FDA scientists that data from trials of other PARP inhibitors in prostate cancer and the TALAPRO-2 trial that we are discussing this afternoon, strongly indicate that “efficacy of PARPi is attenuated, if not absent, in biomarker-negative patients.”
To evaluate the efficacy of this drug combination for patients with negative HRR test results, a larger sample size and adequate power are needed. This is because it is a known predictive biomarker, and most mCRPC patients do not have that biomarker.
We also have Safety concerns from the TALAPRO-2 trial.
The combination of Talzenna and Xtandi led to greater toxicity in patients without genetic mutation than observed in the placebo group, with more incidences of high-grade and serious adverse reactions, which led some to discontinue treatment and reduce dosage.
Further, toxicity in patients without tumor mutations who received Talzenna and Xtandi, increased with age. This affects the risk:benefit ratio for biomarker negative patients, for whom any benefits are not statistically significant and may not be clinically meaningful.
Results also showed that by adding Talzenna to Xtandi in negative biomarker patients, there was increased risk for hematologic toxicity.
There were also higher rates of anemia, attributed to cytopenias (or a lower number of mature blood cells), which led to 52% of patients needing at least one blood transfusion.
Although the incidence of anemia and transfusions decreased over time, likely a result of lower dosage, the higher rate of adverse reactions can still lead to significant consequences for patients, particularly in a first-line disease setting where patients typically display minimal symptoms.
Comparisons across trials raise questions about whether adding Talzenna to Xtandi has a favorable benefit-risk profile in patients without HRRm.
Is this data sufficient to justify expanding the indication to include patients without this genetic mutation?
The reason is that while there were statistically significant improvements in radiologic Progression Free Survival and Overall Survival in Cohort 1, the study design limited the ability to examine the impact on patients without mutations. The study did not include an adequate sample of patients or statistical power to confidently answer that question.
This is important since most patients with mCRPC do not have a HRR mutation.
Just yesterday, Commissioner Makary made it clear that the FDA must not approve a product unless research confirms that the benefits outweigh the risks. It is not at all clear that the benefits outweigh the risks for an expanded indication of Talzenna and Xtandi to patients without the HRRm gene mutation. NCHR strongly recommends that the Applicant further research and explore whether the benefits outweigh the risks for this patient population.