April 30, 2026
I’m Dr. Diana Zuckerman, president of the National Center for Health Research. Our nonprofit research center does not accept funding from companies with a financial interest in our work, so we have no conflicts of interest.
Prior to my current position, I was a post-doc at Yale Medical School, conducted research at Harvard and Yale, and investigated FDA approval decisions for the U.S. Congress. On a personal note, my husband and my Dad were both treated for prostate cancer. Today I will focus on the most important question for the FDA and for patients: Are the results clinically meaningful?
I thank the FDA for focusing on that question and agree with the FDA review that the progression free survival result represents a small treatment effect in the context of previous approvals demonstrating greater effects.
In CAPItello-281, the radiographic progression free survival hazard ratio estimate was 0.81, which was in the middle of the confidence intervals. That raises questions about whether the benefit is meaningful, especially since there was no statistically significant overall survival benefit at the interim analysis. Even for a short-term study, that lack of benefit is still important.
As you have heard, the FDA told AstraZeneca in 2020 that the agency was concerned with the study design and overall survival might be needed to prove the benefit of TRUQAP. Adding a new drug to an effective and well-tolerated therapy makes it difficult to determine the benefits of that additional drug. Had the difference in progression free survival been more substantial, a significantly better overall survival might have been less necessary. However, PFS showed a modest difference that was within the confidence intervals and only significant at the .05 level, which is the minimum considered relevant
What about risks?
We agree with the FDA analysis that the addition of TRUQAP resulted in increased serious toxicities, including early fatal adverse reactions, increased healthcare utilization, and worse patient-reported outcomes such as severe diarrhea and other symptoms that harm quality of life.
As FDA noted, when the patients were enrolled in the study, most had no symptoms or mild symptoms and could have expected 2-3 years without progression of cancer. That’s why adverse events were more problematic than they would have been for patients with more advanced disease. We therefore agree with the FDA that the risks of this drug seem to outweigh the benefits.
There are other shortcomings of the evidence:
- The Control Arm therapy was NOT the triplet therapy that is currently preferred for the enrolled patients.
- Secondary endpoints were based on exploratory studies, so those data should not be used as the basis for FDA approval. And, the differences were again within the confidence intervals, so were not necessarily meaningful.
To earn FDA approval, the magnitude of the treatment effect must be weighed against toxicity. The poor prognosis of this subgroup of patients does not, in and of itself, establish that a modest treatment effect is clinically meaningful.
In conclusion, we agree with the FDA’s concerns that the demonstrated magnitude of improvement in PFS is not proven to be clinically meaningful given
#1. the absence of a benefit on overall survival
#2. the added toxicity, including increased number of early deaths,
#3. the early metastatic disease state being studied, and
Last: the lack of external data supporting meaningful efficacy of this drug OR of any other AKT inhibitors in patients with this type of prostate cancer.
Thank you for the opportunity to speak today.