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Management of Advanced Prostate Cancer Undergoing Major Shift

Eastman, Peggy

doi: 10.1097/01.COT.0000399767.07659.fb


BETHESDA, MD—The treatment of patients with advanced prostate cancer used to be fairly straightforward, but the availability or imminent availability of multiple new therapies is rapidly making that treatment far more complex even as it brings new hope to patients. So said speakers here at the Society of Urologic Oncology Annual Meeting, held on the grounds of the National Institutes of Health.

“We've begun to evolve a paradigm so that we can now layer on therapies,” said Robert Dreicer, MD, MS, Chairman of the Department of Solid Tumor Oncology and Professor of Medicine at the Cleveland Clinic. “We're approaching an era in which advanced prostate cancer becomes a chronic disease.”



He warned that the learning curve for some of the new therapies is going to be steep, and that physicians from numerous specialties—including urology, medical oncology, and radiation oncology—will be treating men with advanced prostate cancer. “It's going to be the Wild West for awhile,” he said. “We're going to have to figure all this out on the fly; it's not going to be an easy journey.”

Dr. Dreicer cited the recently approved immunotherapy sipuleucel-T (Provenge); the investigational vaccine PSA-TRICOM (Prostvac); the investigational monoclonal antibody denosumab, which inhibits RANKL activation of osteoclasts; MDV-3100, an investigational anti-androgen; and abiraterone, an investigational CYP17 inhibitor that lowers testosterone, as examples of new therapies that are going to challenge physicians treating men with advanced prostate cancer even as the agents may extend lives.

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Limitation May Be the Cost

Speaking of Provenge, Dr. Dreicer said, “I can tell you as a urologic oncologist that what my colleagues don't know about this is fairly striking. This is a therapy that has no overt anti-tumor activity in ways that we can see it…..As we begin to integrate these new therapies into treatment, it's going to be about both science and economics; the limitation may be the cost.”

A course of Provenge, which is administrated in three doses, costs more than $90,000. The American Society of Clinical Oncology named Provenge as a notable development in its review of major advances for 2010 (OT,11/25/10), and in November a Medicare advisory panel backed Provenge, which could ultimately help lead to Medicare coverage of the drug.



“Treating advanced prostate cancer used to be relatively straightforward five years ago,” agreed Adam S. Kibel, MD, Professor in the Division of Urologic Surgery at Washington University Medical School in St. Louis, who moderated a session at the meeting on new therapies for prostate cancer. “We now have multiple new agents…It becomes confusing; I don't think it's going to be the Wild West, but it does become more complicated.” Dr. Kibel predicted that a number of newer therapies for advanced prostate cancer will gradually move into earlier treatment phases. “I think a lot of these agents are going to be moving earlier into the disease state,” he said.

Integrated results from three randomized, double-blind, controlled trials show that Provenge has an overall survival benefit of about 4.1 months, as shown in an analysis presented at the SUO meeting. The three trials analyzed included a-symptomatic or minimally symptomatic patients with metastatic castrate-resistant prostate cancer.

The improved survival is good news, but “we're not at a point where we can predict who will respond to Provenge,” said another speaker, Philip W. Kantoff, MD, a coauthor of the analysis, who is Professor in the Department of Medicine at Harvard Medical School and Dana-Farber Cancer Institute. He noted that Provenge appears to work by activating T cells to enhance their tumor-fighting ability.

Dr. Kantoff added that the most common adverse events seen with Provenge include chills, pyrexia, headache, and myalgia. Grade 3 acute infusion reactions, including nausea and vomiting and dizziness, occurred in about 3.5% of patients on the immunotherapy and can be managed in the outpatient setting, he said.

There were no observed Grade 4 or 5 acute infusion reactions, and the incidence of cerebrovascular events was 3.5% in the Provenge group and 2.6% in the control group.

ROBERT DREICER, MD, MS: “We've begun to evolve a paradigm so that we can now layer on therapies…

ROBERT DREICER, MD, MS: “We've begun to evolve a paradigm so that we can now layer on therapies…

Based on promising results of two NCI-funded Phase II trials of Prostvac in advanced prostate cancer reported at the meeting, in which patients on Prostvac on average lived 8.5 months longer in the first study and 9.2 months longer in the second, a global, randomized, controlled Phase III clinical trial is planned for the first half of this year.

The Phase III NCI study will be designed to confirm whether the vaccine can improve overall survival in advanced prostate cancer patients compared with placebo. There are also other ongoing trials of Prostvac at NCI.

In another study reported at the SUO meeting, denosumab significantly delayed the time to a first on-study skeletal-related event in patients with bone metastases from castrate-resistant prostate cancer compared with zoledronic acid.

Denosumab was administered subcutaneously every four weeks, while zoledronic acid was given by intravenous infusion every four weeks. First author Neal D. Shore, MD, Medical Director of the Carolina Urologic Research Center in Myrtle Beach, noted that one advantage of denosumab is that it should not affect the kidneys, unlike zoledronic acid, which is cleared by the kidneys.

Adverse events were consistent in both treatment groups with those that have been reported in populations with advanced cancer. Osteonecrosis of the jaw was higher (2.3%) in patients on denosumab compared with patients on zoledronic acid (1.3%). Overall survival was similar between the two treatment arms.

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Cost Effectiveness for Using Finasteride

In other news from the SUO meeting, a study from researchers at Duke University calculated the most cost-effective strategy for using finasteride as chemoprevention for prostate cancer, noting that cost has been considered a limitation to widespread chemoprevention with finasteride. (The FDA's Oncologic Drugs Advisory Committee recently voted not to recommend use of finasteride as chemoprevention in men age 55 or older with a normal digital rectal examination and a prostate specific antigen reading of 3.0 ng/mL or less—OT, 1/10/11 issue.)

The Duke researchers sought to evaluate the impact of varying age at the start of therapy and length of therapy on the cost-effectiveness of finasteride for chemoprevention.

Using a Markov model with probabilistic sensitivity analysis, the researchers found that the cost-effectiveness of chemoprevention with finasteride was optimal when started at age 65 and continued until age 80.

In that case the incremental cost-effectiveness ratio was $65,600 per quality-adjusted life year. In contrast, when a man started finasteride chemoprevention at age 50, the incremental cost-effectiveness ratio was $86,600 per quality-adjusted life year.

The study found that at each age of starting chemoprevention with finasteride, stopping at age 80 was most cost-effective.

Finally, another study, also from Duke, examined the impact of an abnormal digital rectal examination (DRE) on prostate cancer detection in obese men, who are known to have a higher risk of prostate cancer due to excess body weight.



The study found that obese men are less likely to have an abnormal DRE than non-obese men are, but that an abnormal DRE in an obese man pointed to a greater risk of finding prostate cancer on biopsy than in a man of normal weight.

“Together these findings suggest that prostate cancer detection using DRE is negatively impacted by excess body weight,” the Duke researchers concluded. “And while performing DRE may be technically difficult in morbidly obese men, it should not be neglected because an abnormal DRE is a stronger predictor of prostate cancer among obese men than in non-obese men.”

© 2011 Lippincott Williams & Wilkins, Inc.
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