Integrating New Hormonal Therapies in Advanced Disease

Anita T. Shaffer @Shaffer1
Published: Friday, Jun 10, 2011
Robert Dreicer, MD, MS
Robert Dreicer, MD, MS
Hormonal therapies have long been the standard of care for metastatic advanced prostate cancer, particularly since the rise of prostate-specific antigen (PSA) testing in the 1980s enabled clinicians to treat patients before their disease progressed.

The goal in androgen deprivation therapy (ADT) has been to reduce the levels of testosterone and dihydrotestosterone (DHT). Now, a new generation of hormonal therapies is on the horizon, with the development of novel agents that target androgen receptors (ARs) in an attempt to block the signaling pathways believed to promote the disease.

Robert Dreicer, MD, MS, chairman of the Department of Solid Tumor Oncology at the Taussig Cancer Institute at the Cleveland Clinic and professor of Medicine at the Cleveland Clinic Lerner College of Medicine in Ohio, said the new drugs will present clinicians with fresh options for their patients while raising challenging questions about how best to integrate therapies.

One of the most promising of these options, abiraterone acetate (Zytiga), moved from the horizon to the front lines of prostate cancer care on April 28, when the FDA approved the drug for use in combination with prednisone to treat patients with metastatic castrationresistant prostate cancer (mCRPC) who have received prior chemotherapy containing docetaxel.

Another exciting AR-targeting agent is MDV3100, which is undergoing clinical trials as a second-line therapy for mCRPC, Dreicer said.

Figure. Clinical states in prostate cancer.Although such new drugs may debut as therapies for later-stage cancers, Dreicer said he believes clinicians are likely to start using them earlier in the treatment process. Thus, the timing and interaction of various therapies will become increasingly complex; clinicians, for instance, will have the choice of using not only new hormonal approaches, but also the sipuleucel-T vaccine (Provenge), as well as denosumab (Xgeva) and prednisone (Figure).

“All of these issues are going to be great challenges, and I’m not talking about sometime in the distant future,” Dreicer said. “These are likely to be issues that we’re going to deal with in the next 12 to 24 months. So how to figure this out, how to do it rationally, how to take optimal care of the patient without killing the budget, is going to be a problem. It’s going to get very complicated, and we need to work together to optimally manage patients,” he said.

Rationale for AR Targeting

Even as PSA testing has resulted in far fewer patients turning up in physicians’ offices with de novo metastatic prostate cancer, declines in serum levels that the test can track and that are used to help guide treatment are not mirrored in androgen levels.

In advanced prostate cancer, androgens are produced at 3 critical sites: the testes, the adrenal gland, and in prostate cancer cells. “Increasingly, there is compelling evidence that prostate cancer cells themselves produce testosterone, ultimately becoming a self-fulfilling prophecy in terms of disease progression,” Dreicer said.

Dreicer said testosterone and DHT remain elevated despite castrate serum levels and that AR-signaling pathways are “persistently activated.” He also said a hypersensitive phenotype “renders these cells exquisitely sensitive to extremely low levels of exogenous androgens.”

“Newer and more effective methods of blocking androgen synthesis and/or AR antagonists may have promise as therapeutic agents,” he said, listing as examples lyase inhibitors, second-generation antiandrogens, and dual inhibitors.

Therapies differ in their ability to suppress testosterone. As examples, Dreicer cited declines in testosterone levels in these therapies:

"It’s going to get very complicated, and we need to work together to optimally manage patients."–Robert Dreicer, MD, MS

Abiraterone Gains Approval

Abiraterone acetate is an oral agent that inhibits the dual enzyme complex CYP17 (17 a hydroxylase and C17,20-lyase), which is principally responsible for androgen synthesis. In approving the drug, the FDA said the compound has demonstrated the ability to prolong survival for patients with few treatment options. The agency cited results from a study presented approximately 7 months ago.

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