The FDA’s Gastroenterology & Urology Devices panel yesterday voted against recommending approval of Edap’s (NSDQ:Edap) Ablatherm system for thermal ablation of the prostate gland to treat low-risk, localized prostate cancer.

The panel unanimously voted against Ablatherm’s effectiveness, in majority against the device’s safety (5 no votes, 3 yes votes and 1 abstention) and against its benefits outweighing its risks (8 no votes and 1 abstention).

Ablatherm is a computer-controlled high intensity focused ultrasound (HIFU) medical device that delivers treatment from an endorectal probe under ultrasound visualization and is intended to ablate the entire prostate gland, according to FDA background materials released ahead of the meeting.

While panelists admired the technology used by Ablatherm, they found fault with the study design and the primary endpoint used to demonstrate its effectiveness in the trial. Edap compared 2-year biochemical survival rates for patients treated with Ablatherm to a performance goal derived from cryotherapy literature. The panel said that this was not adequate to show that the device is effective, saying that prostate cancer is often a slow-developing disease that can take up to 20 years to pose a mortality risk.

They also noted high rates of adverse events associated with Ablatherm, including erectile dysfunction and urinary incontinence, clinically significant rates of stricture, urethral injury and bowel injury.  

“I think that to justify the level of morbidity from this experiment you need to see a significant benefit and I think this was a very difficult population in which to do that. And, I’m not sure that you’re going to be able to do that with this population in the future,” said Dr. Phillip Hanno of the Hospital of the University of Pennsylvania.

Prostate cancer is the second most common cause of cancer-related death in U.S. men and is now the leading cause of soft tissue malignancy in men, representing 1/3rd of incident cancer cases, the federal watchdog agency noted. Prostate cancer accounts for 3% of all male deaths. Among patients diagnosed with the disease, 46% are reported as being at low risk, 30% at moderate risk, and 24% at high risk, according to the D’Amico classification. Due to the widespread use of PSA screening in clinical practice, more men are being diagnosed at earlier stages and thus have a lower risk of morbidity and mortality from the disease, the FDA pointed out.

Moving forward, not all is necessarily lost for Edap, even if the FDA follows its panel’s recommendation. After voting against approval of the company’s device, panelists discussed how a trial of the low-risk prostate cancer population could be done better in the future.

"The endpoint should be eradication of disease, but we’re only going to know that 20-30 years down the road, so I don’t think that is reasonable," Arizona Urologic Specialists’ Dr. Susan Kalota said. "I stick with biopsy not because I think that demonstrates that we’ve done benefit to the patient, but in a reasonable time period I think that’s the only way we can judge it if we’ve apparently eradicated the disease locally, that it’s done what it’s supposed to do, and hopefully with time that will demonstrate benefit."

In a different patient population – those with high-risk prostate cancer – recent evidence shows that control of the primary lesion is very important and "hormone therapy alone without radiation therapy of the prostate doesn’t work," John’s Hopkins University’s Dr. Patrick Walsh pointed out. "That’s why removing the prostate in the face of positive nodes may be better, and the recent data suggested that patients with metastatic disease who’ve had treatment of their primary survive longer than ones who don’t.

"The concept is that there’s a pre-metastatic niche to which metastatic cells hone to and that there are circulating factors produced by the prostate that are responsible. The patients who are radiated who have high-risk disease and have a positive biopsy do less well than patients who don’t, and so I don’t think we can ignore the primary and in the future I think there’s lots of options," he noted.

"We are disappointed by the committee’s recommendation regarding Ablatherm-HIFU for the treatment of low-risk, localized prostate cancer and we appreciate the dialogue during today’s meeting," Edap CEO Marc Oczachowski said in prepared remarks. "We look forward to subsequent discussion with the FDA. We will continue to work diligently with the FDA as it carefully completes its final review for Ablatherm-HIFU’s PMA."

There are currently no legally marketed HIFU devices to treat prostate cancer and men with localized prostate cancer are treated either aggressively with radical prostatectomy surgery or radiation or more conservatively with regular monitoring with delayed therapy when warranted. Cryotherapy and hormone therapy are also used on occasion to battle prostate cancer. There is increasing evidence that therapeutic intervention delays disease progression and disease-specific mortality as compared to active surveillance (no treatment) but has little or no effect on overall survival regardless of risk strata, the FDA noted. Despite this, the majority of patients with low-risk prostate cancer still undergo therapeutic intervention either initially or after a relatively short period of active surveillance. Though "no treatment" might be an acceptable option for low risk disease in patients with limited life expectancy, it is widely accepted that there is currently no definitive way to determine which men require treatment and who can be safely managed on active surveillance, the agency said.

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