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 has 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.
Abiraterone acetate and MDV3100 are 2 promising AR-targeting agents under development as second-line therapies for metastatic castrate-resistant prostate cancer (mCRPC), Dreicer said.
If these drugs are approved, 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.
“All of these issues are going to be great challenges and I’m not talking about some time 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 Targets
Even as PSA testing has resulted in far fewer patients turning up in physicians’ offices with de nova 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:
Positive Evidence for Abiraterone Building
Bilateral orchiectomy: testosterone falls to 15 ng/dL (0.5 nmol/L) on average
Luteinizing hormone-releasing hormone agonists: 30-40 ng/dL average range of suppression
Lyase inhibitors: testosterone falls to <1 ng/dL
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 October, 2010, de Bono et al reported results of a large, randomized phase 3 trial that demonstrated a >35% improvement in survival for patients treated with abiraterone. The study results, presented at the 35th Congress of the European Society for Medical Oncology in Milan, Italy, involved 1195 mCRPC patients from 13 countries previously treated with chemotherapy, including docetaxel (Ann Oncol. 2010;21[suppl 8]
: abstract LBA5
). In this study, 797 patients received 1000 mg daily of abiraterone plus the corticosteroid prednisone, while those in the control arm received a daily placebo plus prednisone. The median overall survival for those in the abiraterone arm was 14.8 months versus 10.9 months for the placebo arm.
The adverse event profile also was encouraging. The 3 most frequently reported events were fluid retention, hypokalemia, and cardiac disorders; the incidence of grades 3/4 events among these complaints was 2.3%, 3.8%, and 4.1%, respectively.
“This is unequivocally a positive trial of an oral, well-tolerated therapy,” said Dreicer, adding that results were consistent across subgroups of patients.