Padeliporfin Has Good Results in Low-Risk Prostate Cancer

Becky McCall

March 28, 2011

March 28, 2011 (Vienna, Austria) — Phase 2 study results of padeliporfin (Tookad, Steba Biotech) in patients with low-risk prostate cancer yielded negative biopsies in more than 80% of patients treated.

The product is a bacteriochlorophyll derivative, which, after being activated by light, initiates a cascade of pathophysiologic events that result in the instantaneous occlusion of the entire tumor blood supply, followed by rapid ablation of tumor tissue, said principal investigator Abdel Rahmene Azzouzi, MD, a urologist from the University of Angers, France.

Dr. Azzouzi presented the results of 2 phase 2 studies — P201 (Europe/Canada) and P203 (Europe) — here at the European Association of Urology (EAU) 26th Annual Congress.

The objectives of P201 were to determine the optimal dose and the amount of light energy required to achieve prostate tumor ablation, and to assess the effects in men treated with padeliporfin. P203 was designed to confirm the optimal treatment conditions that had been investigated in a previous phase 2 study. Secondary objectives were to assess the safety and quality of life of patients after treatment with different doses of the product and different amounts of light energy.

Patients in the study had positive prostate biopsies, were eligible for active surveillance, had a Gleason score of less than 3 + 3, and had a prostate-specific antigen (PSA) level below 10 ng/mL. Tumor stages of study participants were up to cT2b – N0/Nx – M0/Mx, but patients who were currently receiving treatment for prostate cancer or who had been treated in the previous 6 months were not included in the study.

The primary end point was a negative biopsy in the treated lobe at 6 months; the secondary end points included a reduced volume of hypoperfusion on magnetic resonance imaging (MRI) on day 7 after treatment and PSA changes from baseline at 6 months.

The P201 Study

The P201 study tested the efficacy of varying doses of padeliporfin, from 2 to 6 mg/kg (depending on prostate volume); laser light at 753 nm with a fixed-energy dose (200 J/cm); fiber lengths from 1 to 4.5 cm of illumination; and increasing the number of fibers from 1 to 16 into the 1 or 2 lobes that were treated.

Of 40 patients initially treated with padeliporfin, 28 received 4 mg/kg, 200 J/cm per fiber, with at least 3 fibers applied, and were available for biopsies at 6 months.

The study assessed the correlation between the total energy delivered and volume of necrosis observed at day 7 on MRI, the definition of optimal conditions, the correlation between MRI (percentage of necrosis) and light density index (LDI), and results of negative biopsies according to a LDI (less than 1 vs more than 1).

Dr. Azzouzi explained that if the extent of necrosis of the prostate tumor is assessed after treatment with an LDI of less than 1, then the mean necrosis was 59%, but if the LDI was increased to greater than 1, then the mean necrosis was 95%.

"According to negative biopsy findings, the best dose of product (4 mg/kg) for optimal conditions of safety and efficacy in this study were found to correspond with an LDI of greater than 1, which was seen in 12 patients, who showed 83% negative biopsies [P = .03]," Dr. Azzouzi reported.

In summary, Dr. Azzouzi said that negative biopsies at 6 months correlated with MRI findings on day 7, which provided the proof of concept that padeliporfin is efficient at achieving focal ablation of tumors. These conditions were found to be 4 mg/kg padeliporfin, 200 J/fiber, at an LDI of greater than 1.

P201 also showed a favorable general safety profile and good quality of life. However, Dr. Azzouzi added that phase 3 studies are needed to confirm the optimal conditions.

The P203 Study

The second phase 2 study, P203, looked at a narrower dose range of padeliporfin (4 to 6 mg/kg), laser light at 753 nm but with a fixed-energy dose of 200 or 300 J/cm fiber, and fiber lengths from 1 to 5 cm of illumination. The number of fibers tested ranged from 3 to 21 into 1 or 2 lobes. Seventeen patients received bilateral treatment at 4 mg/kg and 200 or 300 J/cm, and 47 patients received hemiablation treatment at 4 mg/kg and 200 J/cm.

When optimal conditions were applied (4 mg/kg, 200 J/cm hemiablation), the percentage necrosis corresponding to an LDI greater than 1 was 90%. The percentage of negative biopsies at 6 months under optimal conditions was 82.6%.

"These figures showed excellent reproducibility of results from the P201 study at 6-month biopsy. We also found that the best way to achieve LDI above 1 was through hemiablation; in this case the mean percentage necrosis was 90%," Dr. Azzouzi said.

P203 also looked at safety results, in particular, at erectile function and urinary symptoms. The most commonly observed adverse events were dysuria and lower urinary tract symptoms, hematuria, and disorders related to administration site conditions (e.g., perineal reactions at the point of puncture, discomfort, and hematoma), but all of these resolved.

Study Results

"Quality of life was maintained in P201 with a slight decrease in [International Prostate Symptom Score] and stable [International Index of Erectile Function]. For P203, we see a slight decrease in [International Prostate Symptom Score], but a more important decrease in the [International Index of Erectile Function] score," said Dr. Azzouzi.

"Regarding erectile function in the P203 study, the more important decrease was related to a subgroup of 7 patients. It is not clear if the more important decrease is related to predisposing comorbidities in this group of patients, which led to a more important impact on their erectile function. We are currently looking at these data . . . and should have an answer in the coming weeks," Dr. Azzouzi told Medscape Medical News.

Dr. Azzouzi concluded that padeliporfin is safe with a limited effect on quality of life, and that the procedure is easy and can be safely repeated. "In fact, it is easier than brachytherapy and doesn't need any additional staff in the theater. It's a short procedure — roughly 1 and a half hours. However, a phase 3 trial is required to confirm safety, efficacy, and quality of life," he concluded.

Phase 3 Study

The phase 3 study — A European Randomized Phase 3 Study to Assess the Efficacy and Safety of Tookad Soluble for Low-Risk Prostate Cancer vs Active Surveillance — began a few weeks ago. Approximately 30 centers in 10 European countries (the United Kingdom, Germany, France, the Netherlands, Belgium, Sweden, Denmark, Finland, Spain, and Italy) will perform the study.

Sébastien Crouzet, MD, a urologist at Edouard Herriot Hospital, Lyon, France, said he expects the new phase 3 trial to be exciting. "It's a new way of thinking about prostate cancer. We know prostate cancer screening leads to more findings, but not all will progress to aggressive disease. . . . For those that do, focal treatment may be part of the answer. Phase 3 might show that if we only treat the cancer, we won't actually create more morbidity, but we will still kill the cancer. Patients will be randomized between active surveillance and treatment, and they will be followed-up for 2 years. If any patient, treated or under active surveillance, develops cancer, then they'll receive treatment. It will be interesting to see how treatment affects quality of life, and to see which patients actually go on to develop aggressive disease," he told Medscape Medical News.

Freddie Hamdy, MD, Nuffield Professor of Surgery at University of Oxford, United Kingdom, and chair of the EAU's scientific conference committee, also commented on the treatment. "There's a lot of progress exploring the concept of focal therapy in prostate cancer, and that's based on new technologies that allow treatment of the part of the prostate where the dominant cancers are. These technologies have shown good proof of concept and effect in early-phase trials, and what they now need is evaluation in large cohorts of patients," Dr. Hamdy said.

"They could be promising if they show efficacy. This therapy addresses the fact that we overtreat many patients with early disease who do not want to receive active surveillance. But we are not yet at the stage where we can offer this on a routine basis," he remarked.

Gabriel Haas, MD, formerly chair of the Department of Urology at Upstate Medical University, New York, and active researcher on the epidemiology of prostate cancer, said: "I think it is potentially a very interesting solution for patients with low-grade, small-sized prostate cancer. It's interesting that research related to the development of padeliporfin has shown that patients who had their prostates incidentally removed during an operation for bladder cancer were found to have small tumors. These patients did not have a diagnosis of prostate cancer, yet in a high percentage they did [have the disease]."

"So it is likely that in the population being assessed here, the cancers are probably more significant than suggested by the data, especially if the patients are older, when the tumors are likely to be larger and needed to be looked for," said Dr. Haas.

Dr. Azzouzi was a principal investigator for padeliporfin. Dr. Haas is associated with Astellas Pharma Global development. Dr. Crouzet and Dr. Hamdy have disclosed no relevant financial relationships.

European Association of Urology (EAU) 26th Annual Congress. Presented March 20, 2011.

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