An FDA advisory committee on Wednesday unanimously voted against recommending approval of the PARP inhibitor talazoparib (Talzenna) plus enzalutamide (Xtandi) for all patients with metastatic castration-resistant prostate cancer (mCRPC).
In an 8-0 vote, members of the Oncologic Drugs Advisory Committee (ODAC) said the available data from the TALAPRO-2 trial do not support a favorable risk-benefit profile of talazoparib plus enzalutamide in patients without homologous recombination repair (HRR) gene-mutated mCRPC — the combination is currently approved for the HRR gene-mutated population.
ODAC members raised a number of concerns, including the lack of prespecified formal statistical efficacy testing for the non-HRR population, as well as the lack of supportive data from previous PARP inhibitor trials for this population.
“The TALAPRO study was not powered to study efficacy in patients without HRR mutations. I thought this weakened the strength of the conclusions we could draw,” said panelist Neil Vasan, MD, PhD, of Columbia University Medical Center in New York City.
“As a field, we need to commit to formally evaluating whether targeted therapies benefit patients with and without the biomarkers,” he added. “Simply put, precision oncology demands precision trials.”
In a separate session on Wednesday, ODAC members voted 5-4 that the risks outweighed the benefits of UGN-102, a nonsurgical treatment candidate for recurrent, low-grade non-muscle invasive bladder cancer (NMIBC).
While some were impressed with the product’s high complete response (CR) rate, members said the results from supporting studies (including the single-arm ENVISION trial) left too many unanswered questions concerning the efficacy and safety of UGN-102 — questions that could best be answered by a full randomized trial.
Talazoparib-Enzalutamide for mCRPC
In 2023, the FDA approved talazoparib in combination with the androgen receptor inhibitor enzalutamide for HRR gene-mutated mCRPC based on progression-free survival results from the TALAPRO-2 trial.
Pfizer recently requested an expansion of the indication to all-comers with mCRPC based on overall survival (OS) results in unselected patients that included those without HRR gene-mutated disease — 45.8 months with the combination versus 37 months with enzalutamide alone (HR 0.796, 95% CI 0.661-0.958, P=0.0155).
In briefing documents released ahead of the ODAC meeting, FDA reviewers noted that this would be the first approval of a PARP inhibitor for a biomarker-unselected metastatic prostate cancer indication and raised concerns that TALAPRO-2 was insufficient to support this broad label expansion.
In particular, FDA reviewers were concerned by the lack of prespecified formal statistical testing of efficacy in the population without HRR gene-mutated disease.
Pfizer is asking for “a huge indication — 70% of men with castration-resistant prostate cancer,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence, during the ODAC meeting.
“This is a big population … that really was not tested at all statistically,” he added. “We do not have confidence in what these results are.”
Added side effects, most of which were hematologic, were also a concern among the panelists.
“The toxicity can’t be ignored here,” said member Ravi Madan, MD, of the National Cancer Institute in Bethesda, Maryland. “Just because we can manage a toxicity doesn’t mean it doesn’t impact patients’ lives, even if we warn them about it ahead of time.”
UGN-102 for NMIBC
The standard of care for patients with low-grade, intermediate-risk NMIBC is transurethral resection of the bladder tumor (TURBT).
However, ENVISION investigator Max Kates, MD, of the Johns Hopkins Greenberg Bladder Cancer Institute in Baltimore, pointed out that this is a highly recurrent disease where many patients are burdened with repeated procedures that “do not effectively treat their cancer.”
Thus, he added, there is an unmet need for a non-surgical option for these patients.
In ENVISION, the FDA analysis showed a 3-month CR rate of 77.6% among the 223 patients treated with UGN-102. Of those, 79.2% had responses lasting a year or beyond.
However, FDA staffers said that in a single-arm trial it was unclear if that observed duration of response was due to the effect of UGN-102 or natural disease history. In addition, FDA staff said that genitourinary symptoms were greater with UGN-102 than with TURBT.
UGN-102 was also evaluated in the randomized ATLAS trial, which compared UGN-102 with or without TURBT to TURBT alone. Preliminary results from the study demonstrated higher CR rates with UGN-102, but the trial was stopped early and FDA staff said it considered the results exploratory only.
“Without a full randomized trial … it’s very hard to determine the true benefit of this,” said Daniel Spratt, MD, of Case Western Reserve University in Cleveland, who chaired the day’s two sessions. “While I understand from the experts in this field that a 3-month CR rate is kind of a standard in this field … the follow-up to me is far too short in this indolent disease process to know how this will impact subsequent salvage therapies.”
Members voting in support of the product called the response rate an encouraging sign of the treatment’s efficacy, particularly for patients dealing with the burden of having to undergo repeated TURBTs.
“A fully enrolled randomized controlled trial would have mitigated many of the critiques, and I think would have made the sponsor’s application a lot stronger,” said Mark Ball, MD, of the National Cancer Institute’s Urologic Oncology Branch in Bethesda, Maryland. “Regardless, even the demonstrated efficacy at 3 months — a reflection of a non-surgical intervention to treat this disease state — is encouraging. And the signal at 12 months and beyond, even though there are differences in interpretation of the data, is quite encouraging.”
Ball also said he did not find UGN-102’s toxicity profile alarming.
Isla Garraway, MD, PhD, of the University of California Los Angeles, who also voted in favor of UGN-102, called the therapy “a very important option for select patients who have significant comorbidity and [who] are not ideal surgical candidates.”
“Any time you can delay surgery or prevent surgery is a win for everyone,” she added.
While not bound by advisory committee recommendations, the FDA usually follows their advice.
Please enable JavaScript to view the