WASHINGTON, DC—The newly approved Provenge prostate cancer therapeutic vaccine was called a new paradigm in oncology by speakers here at the 10th International Congress on Genitourinary Malignancies. “This opens up a whole new era in the treatment of prostate cancer, and moreover, of cancer in general,” said Phillip Kantoff, MD, Professor of Medicine at Harvard Medical School, and Director of the Lank Center for Genitourinary Oncology and Chief of the Solid Tumor Oncology Division at Dana-Farber Cancer Institute.
“This is the first active immunotherapy to demonstrate improved survival,” he added, noting that therapeutic prostate cancer vaccines have been under development for almost 15 years.
Educational grants for the conference were provided by Provenge's manufacturer, Dendreon Corporation, and by sanofi-aventis.
The vaccine (sipuleucel-T), approved by the FDA at the end of April, is an autologous cellular immunotherapy for the treatment of men with asymptomatic or minimally asymptomatic metastatic hormone-refractory prostate cancer.
The vaccine is designed to induce an immune response against prostatic acid phosphatase (PAP), an antigen expressed by most prostate cancers. The vaccine involves leukapheresis, is made from the patient's antigen-presenting cells and is given over a period of about four weeks.
Three Phase III studies involving approximately 700 patients showed “fairly similar results” that led to the approval of sipuleucel-T, said Dr. Kantoff, who cited as pivotal the multicenter IMPACT (Immunotherapy for Prostate AdenoCarcinoma Treatment) trial of some 500 patients, in which the vaccine extended median survival by about four months and reduced the risk of death by 22.5%.
“I think the ideal place to use this agent is in the pre-chemotherapy setting, although it has been approved post-chemotherapy,” said Dr. Kantoff. One important research issue to be explored, he said, is whether biomarkers can be developed that will predict response to the therapeutic vaccine.
“I've read all the literature on PROVENGE, and I've ultimately become convinced that it works; I just don't know why,” Otis W. Brawley, MD, Chief Medical Officer and Executive Vice President of the American Cancer Society, told OT.
Asked about the cost of the vaccine—which reportedly can be as high as $90,000 a year—Dr. Brawley, who is also Professor of Hematology, Oncology, Medicine and Epidemiology at Emory University, said, “I don't get into costs. I could justify spending money on Provenge; we waste money like crazy on things that we know don't work.”
Second Prostate Cancer Vaccine
Dr. Kantoff said a large Phase III trial of a second prostate cancer therapeutic vaccine, Prostvac-VF, should begin later this year. That vaccine—also for patients with metastatic prostate cancer—was developed by Jeffrey Schlom, PhD, Chief of the Laboratory of Tumor Immunology and Biology at the National Cancer Institute's Center for Cancer Research.
Prostvac-VF makes use of weakened poxviruses such as vaccinia and fowlpox. “Vaccinia is used as an immunological priming agent; PSA is the target,” Dr. Kantoff explained, noting that there have been many clinical trials with Prostvac-VF, and that it has documented immunogenicity and a good safety profile.
In a randomized Phase II study in which Dr. Kantoff participated as principal investigator, two weakened poxviruses were genetically programmed to produce irregular versions of PSA and were used with three co-stimulatory molecules to boost a patient's immune system to attack prostate cancer cells. This trial showed prolonged survival; the median survival of the vaccine group was 24.5 months, compared with 16 months for the control group.
So far, the most common reported side effects with prostate cancer therapeutic vaccines have been fatigue, chills, fever, back pain, and injection-site reactions. Dendreon has reported that severe (Grade 3) acute infusion reactions occurred in clinical trials in 3.5% of patients in the Provenge group. No Grade 4 or 5 acute infusion reactions were reported in patients in the vaccine group.
As part of FDA's post-marketing requirements, Dendreon will conduct a registry of about 1,500 patients on the vaccine to further evaluate what the company calls “a small potential safety signal of cerebrovascular events.” In four randomized clinical trials of Provenge in prostate cancer patients, cerebrovascular events were seen in 3.5% of patients on the vaccine compared with 2.6% of control subjects.
Prostate Cancer Foundation
When Provenge was approved by the FDA, the Prostate Cancer Foundation hailed it as a “breakout” treatment for prostate cancer patients—not a “breakthrough” treatment, which would represent a cure. Since 1993 the foundation has invested about $2 million in support of dendritic cell vaccines and immunotherapy research. The foundation stated its hope that approval of the therapeutic vaccine would boost the likelihood that a preventive vaccine for prostate cancer will one day be developed.
CMS Requesting Comments
While the arrival of prostate cancer vaccines is a major step forward in clinical treatment for men with advanced disease, attendees at the meeting expressed concern in informal conversation about the costs of the vaccine for their patients.
The Centers for Medicare and Medicaid Services has instituted a national coverage analysis, and is requesting public comments on the effects of the vaccine on health outcomes in prostate cancer patients taking it. The coverage analysis does not represent a change in Medicare coverage, nor does it restrict the individual insurance carriers that make up the Medicare program from covering the vaccine.
New CMS Administrator Donald Berwick, MD, co-founder of the not-for-profit Institute for Healthcare Improvement, is known for his studies on how the US health care system can provide high-quality health care at lower cost. Prostate cancer therapeutic vaccines are just one of the costly new medical technologies CMS will be facing in its coverage decisions in the coming years.
Dendreon plans to make Provenge available through about 50 centers that were approved vaccine clinical trial sites, and expects to expand its vaccine delivery capability over the next year through new facilities. The company said it is donating funds to an independent nonprofit organization that will provide financial help to prostate cancer patients who cannot afford the co-pays linked to their medicines, and will also try to match patients to other foundations that can provide financial aid.
Other Prostate Cancer News
In other prostate cancer news from the genitourinary congress, Oliver Sartor, MD, the Piltz Professor of Cancer Research in the Departments of Medicine and Urology at Tulane University School of Medicine and Co-Program Director of the Congress, hailed the availability of a newly approved taxane, cabazitaxel, for hormone-resistant metastatic prostate cancer patients previously treated with a docetaxel regimen and for whom little else has been available. Cabazitaxel binds to and stabilizes tubulin.
“For many years docetaxel was the only chemotherapy approved for castrate-resistant prostate cancer,” Dr. Sartor said. “These are patients where you say, ‘What am I going to do for you now?’ In experienced hands I think this drug [cabazitaxel] is going to be fine.”
Dr. Sartor said the key for advanced prostate cancer patients will most likely be multiple agents. “Clearly multiple drugs will be necessary to cure castrate-resistant prostate cancer, and that is our greatest challenge. How do we target cancers that are heterogeneous in both genotype and phenotype in the same patient?”
Several speakers stressed the importance of discussing the use of 5 alpha-reductase inhibitors (finasteride, dutasteride) with patients who are at lower risk for prostate cancer as well as at higher risk to prevent the disease.
“It is logical and persuasive for urologists to prevent as well as to detect and treat,” said Gerald L. Andriole, MD, the Robert K. Royce Distinguished Professor and Chief of Urologic Surgery at Siteman Cancer Center, Barnes-Jewish Hospital, Washington University School of Medicine. Dr. Andriole said 5 alpha-reductase inhibitors reduce prostate cancer risk, improve the ability of PSA to detect cancer, and are unlikely to promote aggressive cancer.
Dr. Brawley noted that one major benefit of 5 alpha-reductase inhibitors is that they reduce lower urinary tract symptoms, such as difficulty starting a urinary stream. But, he noted, men must be willing to consider experiencing possible side effects (present in very small numbers), such as loss of libido and impotence, a noticeable decrease in ejaculate volume on intercourse, and breast tenderness.
Study: Physicians Reluctant to Use Chemoprevention for Prostate Cancer
Despite the results of the Prostate Cancer Prevention Trial (PCPT) that showed a significant reduction in prostate cancer among those taking finasteride, physicians have not increased its use. That is the conclusion of a study in the September issue of Cancer Epidemiology, Biomarkers & Prevention.
As a news release from the AACR notes, the first results of the trial were published in 2003 in the New England Journal of Medicine and were widely reported. The randomized controlled trial consisted of 18,000 men and showed a 25% reduced risk of prostate cancer.
It also showed, though, a 27% increased risk in high-grade tumors, which was noted in an accompanying editorial. The study's lead author, Ian Thompson, MD, Chairman of the Department of Urology at the University of Texas Health Science Center, said the editorial may have colored the perception of finasteride.
“People tend to read editorials more than they read actual journal articles,” Dr. Thompson said. “The study paradox of a reduction in overall disease but an increase in high-grade disease was not explored until much later.”
In 2008, another report was published in Cancer Prevention Research, also published by AACR, where Dr. Thompson and colleagues reanalyzed the data along with the available tumor biopsies. Results showed that finasteride did not actually increase risk; it just made the available testing more sensitive. This result confirmed the benefits of finasteride for prostate cancer prevention.
In the new study assessing usage, Linda Kinsinger, MD, MPH, Chief Consultant for Preventive Medicine at the Veterans Health Administration National Center for Health Promotion and Disease Prevention, and colleagues surveyed 325 urologists and 1,200 primary care physicians to determine their prescribing patterns. Although the number of men starting finasteride grew over a five-year period, the publication of PCPT did not influence their decision.
Fifty-seven percent of urologists and 40% of primary care physicians said they prescribed finasteride more often; only 2% said they had been influenced by the findings in PCPT.
In fact, 64% of urologists and 80% of primary care physicians never prescribe finasteride for chemoprevention, the analysis found. When asked for reasons for their decision, 55% said they were concerned about the risk of high-grade tumors and 52% said they did not know it could be used for chemoprevention.
“The use of finasteride for prostate cancer prevention does not appear to be widely endorsed,” Dr. Kinsinger said. “The concept of chemoprevention is a difficult one for patients and physicians.”
Similarly for breast cancer, the news release notes—at this year's AACR Annual Meeting, researchers presented results of the STAR trial, which showed a reduction in breast cancer with raloxifene use. In turn, experts discussed the implications of raloxifene for breast cancer prevention. Scott Lippman, MD, Chair of the Department of Thoracic/Head and Neck Medical Oncology at MD Anderson Cancer Center and Editor-in-Chief of Cancer Prevention Research, and AACR President-Elect Judy E. Garber, MD, MPH, Director of the Cancer Risk and Prevention Program at Dana-Farber Cancer Institute, said the public needs to think about agents like raloxifene in the same way that they would think about statins in heart disease prevention.
Dr. Thompson said the statin-to-chemoprevention analogy is a good one, but presents an important challenge: “Statins lower heart disease by reducing blood cholesterol and affecting other lipids, effects which are easy to measure, but there is no equivalent biomarker for cancer prevention. With cholesterol, for example, you can tell that the statin is working. With a cancer chemoprevention agent, you cannot measure success except with the absence of cancer, which you weren't expecting to get anyway.”
He agreed, though, that chemoprevention is an important new frontier that needs continued emphasis.