FDA's ODAC Votes Against Targeted Therapies in Bladder and Prostate Cancer

The FDA’s advisory panel voted against expanded use of Talzenna/Xtandi for prostate cancer and UGN-102 for recurrent bladder cancer, citing safety and efficacy concerns.

The United States Food and Drug Administration's (FDA) Oncologic Drugs Advisory Committee (ODAC) has casted their votes on the utilization of two cancer therapies for the treatment of both non–homologous recombination repair (HRR)–mutant metastatic castration-resistant prostate cancer (mCRPC) and recurrent, low-grade, intermediate-risk non-muscle-invasive bladder cancer (NMIBC) patient populations, respectively.

According to the official United States FDA website (www.fda.gov), the ODAC functions as an expert panel that evaluates clinical data on the safety and efficacy of both investigational and approved drug products intended for cancer treatment. Based on its assessments, the committee offers recommendations to the United States FDA Commissioner to support regulatory decision-making.

As noted on the website, the committee consists of 13 voting members chosen for their expertise in areas such as general oncology, pediatric oncology, hematologic oncology, immunologic oncology, biostatistics and related fields. In addition, the committee may include a non-voting representative from the pharmaceutical industry, who contributes an industry viewpoint to the discussion without participating in the voting process.

Recently, the ODAC hosted a regulatory meeting in which they casted their votes for the risk/benefit profile of two cancer therapies.

For patients with non-HRR-mutated mCRPC, the panel unanimously voted eight to zero against the risk/benefit profile of Talzenna (talazoparib) when combined with Xtandi (enzalutamide), based on data from the phase 3 TALAPRO-2 trial.

Additionally, the ODAC also voted five to four against the risk/benefit profile of UGN-102 (mitomycin for intravesical [within the bladder] solution) in patients with recurrent, low-grade, intermediate-risk NMIBC, based on data from the phase 3 ENVISION and ATLAS trials.

Here is what you need to know about each regulatory decision from the FDA's ODAC.

ODAC's Vote on the Risk/Benefit Profile of Talzenna/Xtandi in non-HRR-Mutant mCRPC

Although the ODAC voted unanimously against the risk/benefit profile of Talzenna plus Xtandi in non-HRR-mutant mCRPC, the treatment combination is currently FDA-approved for the HRR-mutated mCRPC patient population, based on the TALAPRO-2 trial results, as of June 2023. However, following this approval, a supplemental new drug application was submitted to the regulatory agency seeking approval for the treatment combination in the all-comers mCRPC patient population, meaning the approval would not be limited to HRR mutation status.

Of the 1,018 patients with first-line mCRPC who were enrolled in the TALAPRO-2 trial, 805 were a part of the HRR-unselected population and 230 were a part of the HRR-mutated only population. Patients in the HRR-mutated population showed a significant radiographic progression-free survival and overall survival benefit with the Talzenna plus Xtandi treatment. Contrarily, in the HRR-unselected population, although a radiographic progression-free survival benefit was observed, the overall survival benefit was less defined.

The FDA cited concerns that the non-HRR–mutated/unknown subgroup was not completely defined, nor was it formally tested for efficacy. Moreover, the regulatory agency emphasized that therapies in biomarker-negative populations must be more formally evaluated.

There was also increased toxicity observed with the investigative combination in the non-mutated patient group, including higher rates of grade 3 (severe) and 4 (life-threatening) side effects, serious treatment-related events and red blood cell transfusions. There were also incidences of myelodysplastic syndrome and acute myeloid leukemia — effects of treatment —reported.

It is based on these less effective outcomes in the non-HRR–mutated/unknown patient population, as well as the increased toxicity, that the ODAC voted against the risk/benefit profile of Talzenna plus Xtandi in non-HRR-mutant mCRPC.

ODAC's Vote on the Risk/Benefit Profile of UGN-102 in Recurrent, Low-Grade, Intermediate-Risk NMIBC

On the same day, the FDA's ODAC voted five to four against the overall risk/benefit profile of UGN-102 for the treatment of recurrent, low-grade, intermediate-risk NMIBC. This comes after a new drug application was submitted by UroGen Pharma to the FDA in August 2024 for treatment with UGN-102 in this patient population; data from the phase 3 ENVISION trial and the ATLAS study supported the application.

During the meeting, various experts voiced their support and hesitation for voting for or against treatment with UGN-102. Those who voted against the treatment touched on the short three-month complete response end point and lack of a full randomized trial, while those who voted in favor of the treatment highlighted that UGN-102 has the possibility to benefit patients who are not optimal surgical candidates, noting the drug’s potential to delay or avoid surgery.

“While we are disappointed by today’s outcome, we continue to believe our clinical data support UGN-102 for the treatment of recurrent LG-IR-NMIBC, a disease with no FDA-approved therapies,” Liz Barrett, president and CEO of UroGen, said in a news release following the vote from the FDA's ODAC. “The FDA carefully considers the independent advice from ODAC, and we look forward to working with the FDA as they complete their review of the application for UGN-102.”

Notably, the ATLAS study was terminated early, and ENVISION data became the primary evidence for new drug application submission. In the ENVISION trial, patients with low-grade, intermediate-risk NMIBC were treated with weekly instillations of UGN-102 for 6 weeks and achieved a 79.6% complete rate at three months. Additionally, the 12-month duration of response was 82.3%, and regarding safety, most side effects were mild to moderate, with dysuria as the most common event.

There are currently no FDA-approved therapies that currently exist for this patient population.

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