"Dramatic Outcomes" in Prostate Cancer Study, But Only 2 Patients So Far

Zosia Chustecka

June 23, 2009

June 23, 2009 — Mayo Clinic researchers have reported "dramatic outcomes" in a prostate cancer trial. The news was picked up by many media outlets, and even made the front page of a British newspaper with a headline proclaiming Cancer: shock breakthrough.

But the news is based on results from only 2 patients.

However exciting the news, the fact that the results are from only 2 patients makes them "very preliminary," Anthony Smith, MD, professor and chief of urology at the University of New Mexico School of Medicine in Albuquerque, told Medscape Oncology.

Both patients had advanced prostate cancer that was considered inoperable and were participating in a phase 2 clinical trial of the investigational product ipilimumab, an antibody that targets cytotoxic T lymphocytes. They received androgen ablation therapy and then a single dose of ipilimumab. Both of the patients showed a dramatic reduction in tumor size on magnetic resonance imaging and a drop in the prostate-specific antigen levels. After some discussion with the physicians involved, the 2 patients then left the trial and went on to have surgery.

But the operations turned up a surprise, according to a report on the Mayo Clinic Discovery's Edge Web site.

"I was cutting away scar tissue, trying to find cancer cells. The pathologist was checking samples as we proceeded and sent word back asking if we had the right patient. He had a hard time finding any cancer," said surgeon Michael Blute, MD, urologist at the Mayo Clinic in Rochester, Minnesota, and coinvestigator on the trial.

I had never seen anything like this before. The pathologists were floored.

"I had never seen anything like this before. The pathologists were floored," he added.

With the second patient, there were 2 phone calls back from the pathologists, again checking if the correct patient was undergoing surgery.

One of the patients went on to receive radiation therapy after the surgery. Both patients return to the Mayo Clinic for regular follow-up, but both are "free of cancer" and "feel fine," according to the report. However, no details were given of the time frame involved or how many other patients had been treated.

The Mayo researchers said the results from these 2 patients need to be validated in further studies, and plans are underway to extend the trials.

Approached for comment, Dr. Smith said that the results are "pretty interesting," but he also cautioned that many early trials that appear highly promising do not pan out once larger numbers of patients are involved. He wondered whether the enthusiasm over these preliminary results is "a little over the top."

Another expert approached for comment, Kevin Kelly, DO, associate professor of medicine and head of the prostate and urologic cancers program at Yale University in New Haven, Connecticut, said the findings were "very interesting, but it is hard to make anything out of 2 cases."

Another Trial in Prostate Cancer

The Mayo Clinic release did not give any further details about the trial in which these 2 men were participating, but presumably it is the one identified as NCT00170157 on the National Institutes of Health website www.clinicaltrials.gov. This is a phase 2 trial in 108 patients that compares androgen ablative therapy (with leuprolide 7. 5 mg monthly and bicalutomide 50 mg daily, both given for 3 months) with androgen ablative therapy plus ipilimumab (given as a single dose of 3 mg/kg).

Another phase 2 trial with ipilimumab in prostate cancer is ongoing, and the investigators reported their "initial experience" at a poster session during the recent annual meeting of the American Society of Clinical Oncology (abstract 5138). However, there was no publicity about these results, even though there also appeared to be a dramatic outcome in 1 patient in this trial.

First author Susan Slovin, MD, from the Memorial Sloan-Kettering Cancer Center, in New York City, and researchers from other institutions, as well as Medarex, reported their initial experience from 45 patients with metastatic castration-resistant prostate cancer who were treated with ipilimumab, either alone or in combination with radiotherapy.

In the abstract, they report that 10 of 45 patients (22%) had confirmed PSA declines of 50% or more and note that the median time to PSA decline was 5.7 weeks (range, 3 – 21 weeks). In 1 patient who received ipilimumab alone, the PSA level became undetectable (< 0.05 ng/mL), and this patient also showed a complete response of bone, nodal, and prostate lesions; these responses have been maintained for 54+ weeks and 84+ weeks, respectively.

Dr Slovin and colleagues comment that further study of ipilimumab in metastatic castration-resistant prostate cancer is warranted, with or without radiotherapy. They also note that the time to response can be delayed, with a durable median response of 23 weeks.

Stimulates Immune Response?

Ipilimumab is a fully human antibody that binds to cytotoxic T lymphocyte-associated antigen 4, a molecule on T cells that plays a critical role in regulating natural immune responses, according to the manufacturer, Medarex.

The product is not on the market yet, but is in clinical trials in other cancers, including melanoma and lung cancer. Results from phase 2 clinical trials in melanoma were discussed at the American Society for Clinical Oncology meeting last year, as reported by Medscape Oncology. One expert explained that patients were showing a pattern of responses that had never been seen before; another noted that the responses were different from those seen with chemotherapy, so different criteria to measure clinical activity and long-term benefit are needed. "Ipilimumab involves immune activation that begins early and builds an immune response over time," said Stephen Hodi, MD, from the Dana-Farber Cancer Institute in Boston, Massachusetts.

Mayo investigator Dr. Blute said "it's important for us to understand the mechanism of favorable response in these patients." He suggested that the findings could have implications for other forms of cancer, including hormone-sensitive forms, such as breast and ovarian cancer.

Medarex issued a news release commenting on the 2 ipilimumab patients from the Mayo Clinic Trial. Both patients had "aggressive tumors that had grown well beyond the prostate into the abdominal area," the company noted. The news release explained that they received androgen-deprivation therapy, which removes testosterone and usually causes some initial reduction in tumor size. The patients then received a single dose of ipilimumab (administered by intravenous infusion over about 3 hours). This antibody "builds on the antitumor action of the hormone and causes a much larger immune response, resulting in massive death of the tumor cells," according to Medarex.

The prostate cancer trial conducted at the Mayo Clinic was investigator initiated and funded by the institution and the US Department of Defense, but Medarex supplied the drug free of charge and supported safety monitoring during the trial.

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