On February 26, 2020 an FDA advisory committee reported that it voted 2-13 against recommending approval of padeliporfin di-potassium, a minimally invasive treatment for localized prostate cancer (Press release, US FDA, FEB 26, 2020, View Source [SID1234591387]).
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The vote by the Oncologic Drugs Advisory Committee, or ODAC, indicates the panel does not believe the treatment has a favorable benefit-risk profile for this group of men with low-risk disease.
Many panel members expressed concern that men with very low-risk disease would choose this therapy instead of active surveillance, despite the unproven long-term benefits and harms of the treatment.
"For the true low-risk patients who were eligible for the study [of this therapy], I strongly prefer active surveillance for their treatment," Howard Sandler, MD, MS, FASTRO, FASCO, professor and chair in the department of radiation oncology at Cedars-Sinai Medical Center, said during the committee discussion. "For patients who — for whatever reason — don’t want active surveillance, I think they should have proven anticancer therapy with surgery or radiation. I’m not sure that a treatment that has some risk for morbidity is an ideal option for someone with a cancer that doesn’t need any treatment."
Padeliporfin di-potassium (Steba Biotech), also called Tookad Vascular-Targeted Photodynamic (VTP) therapy, is a partial gland ablation treatment that targets half of the prostate to eliminate cancer while preserving surrounding normal tissue to reduce toxicity and improve quality of life for men with early-stage prostate cancer.
Tookad is under evaluation for men with stage T1 to T2a prostate cancer with a PSA less than 10 ng/mL and Gleason grade group 1 disease based on transrectal ultrasound (TRUS) biopsy or unilateral Gleason grade group 2 disease based on multiparametric-MRI-targeted biopsy with less than 50% of positive cores.
In making its decision, the ODAC panel reviewed efficacy and safety data from the phase 3 PCM301 study, which compared Tookad VTP with active surveillance among 413 men (mean age, 63.5 years) with early-stage prostate cancer over 2 years of follow-up.
The rate of absence of definite cancer based on histology at 24 months and the difference in rate of treatment failure, defined as the progression of disease from low- to moderate- or high-risk prostate cancer, served as the study’s coprimary endpoints.
Results showed that the study met both endpoints. Overall, 28.2% of patients assigned Tookad VTP experienced local progression at 24 months compared with 58% of patients assigned active surveillance, for a 66% risk reduction (HR = 0.34; 95% CI, 0.25-0.47).
Forty-nine percent of patients assigned Tookad VTP achieved absence of prostate cancer compared with 13.5% of the control group (RR = 3.6; 95% CI, 2.5-5.26).
However, these data may not be accurate, as the rate of missed biopsy at 24 months was 18% for the treatment group and 42% for the control group. This included 13% of patients in the treatment group and 15% in the control group who had missing biopsies at 24 months for reasons other than having undergone definitive therapy.
"Both primary endpoints of PCM301 rely on accuracy and reliability of biopsies," the FDA wrote in its background briefing materials. "Given that many patients had missing data (13%) or false-negative biopsies (13.5% on the active surveillance arm), potential for errors in pathologic grading due to sampling error, the reliability of results and the difference in magnitude of effect in the two arms is of concern."
The ODAC panel also weighed the greater risk for toxicity observed in the Tookad VTP group.
More men assigned Tookad VTP experienced any-grade adverse events (95% vs. 55%) and grade 3 to grade 4 adverse events (22% vs. 10%).
Specifically, a greater proportion of men assigned Tookad VTP experienced erectile dysfunction (38% vs. 12%) — which was left unresolved at 2 years more frequently in the treatment group (23% vs. 10%) — hematuria (28% vs. 3%), dysuria (27% vs. 2%), and urinary retention (16% vs. 1%) and incontinence (15% vs. 7%).
Ultimately, although many panel members expressed enthusiasm about the potential future role of focal therapy for prostate cancer, they found the limitations of the current analysis prohibitive in recommending approval of the therapy for men with low-risk disease.
"I think if we — on less-than-good evidence — approve this, it could cause more harm than good," Patrick C. Walsh, MD, university distinguished service professor emeritus at James Buchanan Brady Urological Institute of Johns Hopkins Hospital, said during the committee discussion. "I could tell these patients we don’t have to do anything, we can follow you, or we can give you this treatment and in 2 years you still have 50% chance you’re going to have cancer and 28% chance it’s going to be progressing. But, I don’t think that is what patients will hear. Many doctors out there are in business, and this will be an opportunity that will be misused.
"We can’t speed up the time clock today," Walsh added. "These are 2-year data, and I don’t think they are enough to permit so many patients to have a treatment that we don’t know whether or not is working well." – by Alexandra Todak