FDA Panel: Thumbs Down for Prostate Cancer Focal Therapy - MedPage Today

SILVER SPRING, Md. -- A light-activated focal therapy for early prostate cancer failed to win over an FDA advisory committee in a bid for market approval.

By a 13-2 vote, the Oncologic Drugs Advisory Committee (ODAC) declined to recommend TOOKAD VTP for approval. The FDA is not bound by committee decisions but follows the recommendations more often than not.

TOOKAD, developed by Luxembourg-based Steba Biotech, consists of an infusion of padeliporfin di-potassium (derived from an aquatic bacteria), followed by intraprostatic laser activation. Activated TOOKAD leads to a cascade of events involving oxygen radicals, hypoxia, nitric oxide radicals, and endothelin-1, which causes vascular occlusion and, ultimately, self-propagating tumor cell necrosis.

Questions about the therapy's pivotal trial design, endpoints, missing data, and adverse events all contributed to the negative vote. Nonetheless, some ODAC panelists expressed ambivalence about their votes.

"I get the sense that we all somewhat shared the fence-sitting about some of the potential positives of focal therapy for a disease that, until recently, hasn't had much focal therapy," said ODAC chair Philip Hoffman, MD, of the University of Chicago, who cast one of the two yes votes. "But we recognized the limitations of this study, the variability of biopsy reports, surprising results of some of the biopsies despite the therapy. I think this led the majority of people to vote no."

"It may well be in the coming years, as more data accumulate ... the vote may completely turn around as there is more clear data about this," he added.

Other members of the panel were less sanguine about the treatment or its future.

"I see a lot of patients for second opinions," said Patrick Walsh, MD, of Johns Hopkins Medical Center in Baltimore. "I'm very confident in low-risk disease with offering active surveillance because of the data we have at Hopkins. For over 18 years and 1,800 patients with low-risk disease, 0.6% developed metastases and 0.1% died."

"Contrary to that, many patients come to me frightened to death," he said. "Their doctors told them they have cancer and they need to be treated. I think that if we -- on less than good evidence -- approve this, this is something that could cause more harm than good."

Musing about the meaning of statistical significance, Walsh quoted author Gertrude Stein: "A difference, to be a difference, must make a difference."

"I think most of these patients [treated with TOOKAD] won't be told that at 2 years half of the men will still have cancer and in 28% it will be progressing ... I think there are many doctors out there who are in business, and this will be an opportunity that will be misused," said Walsh.

Added Daniel Song, MD, also of Johns Hopkins, "I definitely feel that when you let the genie out of the bottle, this is definitely going to be misused." Still, he counted himself as one of those on the fence: "I could see how this would be beneficial to some patients, but not the ones in this study, as demonstrated here," he said.

Maha Hussain, MD, of Northwestern University Feinberg School of Medicine in Chicago, suggested that focal treatments such as TOOKAD may actually add to patients' confusion about options for low-risk prostate cancer, including active surveillance: "How do you justify saying to patients, 'I don't think you really need a treatment and we really should just watch you, but by the way, we're just going to give you a sprinkle of a treatment?'"

Discussion of the pros and cons of the treatment centered on the primary supporting evidence for the approval application, a phase III randomized, open-label trial comparing TOOKAD and active surveillance in 413 men with newly diagnosed, localized, low-risk prostate cancer.

The trial had two coprimary endpoints and met both of them:

• Absence of prostate cancer at 24 months (49.0% vs 13.5%, P<0.001)

• Freedom from progression from low- to intermediate- or high-risk disease (28.2% vs 58.5%, P<0.001)

An FDA staff analysis cited several issues with the trial design and data. With regard to the first endpoint, FDA staff noted that its "clinical meaningfulness in early-stage prostate cancer is unknown." The second endpoint "has not been previously used as an endpoint for regulatory approval, partially based on lack of validated data." The report also questioned the reliability of biopsies obtained following TOOKAD treatment, which causes scarring.

With regard to toxicity, the report noted that patients on active surveillance did not encounter treatment-related adverse events until disease progression, whereas the TOOKAD group was exposed to potential toxicities at the time of treatment. Additionally, FDA staff noted a substantial disparity in toxicity reporting for patients in active surveillance who underwent definitive therapy as compared with patients randomized to TOOKAD.

Finally, staff noted that Steba, with input from the FDA, has designed another trial to compare TOOKAD and active surveillance with a primary endpoint of objective progression at 30 months. The staff report questioned whether the decision about the treatment should be deferred until completion of that trial -- which, according to its Clinicaltrials.gov listing, is estimated to be in 2030.

The report concluded with the question: "Do the results of PCM301 represent a favorable benefit/risk profile for TOOKAD in patients with low-risk early-stage prostate cancer?"

Steba's briefing document for the committee emphasized that TOOKAD fills a treatment void: "Active surveillance can defer the need for radical therapy but only temporarily for many men. These patients need alternatives that target the cancer area and preserve the surrounding tissues and, consequently, quality of life."

"In the pivotal study, TOOKAD VTP (vascular-targeted photodynamic therapy) resulted in an increase in the probability of a negative prostate biopsy at 24 months after treatment compared to active surveillance and a statistically significant reduction in local disease progression," the report stated. "Multiple sensitivity analyses confirmed the robustness of the time to progression endpoint. Importantly, the treatment with TOOKAD VTP also reduced the rate of conversion to radical therapy compared with active surveillance, which predicts a reduction in the morbidities of radical therapy and shows a clear benefit for patients."