Integrating New Hormonal Therapies in Advanced Disease

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:

• 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

Positive Evidence for Abiraterone Building

Abiraterone acetate is an oral agent that inhibits the dual enzyme complex, CYP17 (17 a hydroxylase and C_17,20-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.

In December, 2010, Centocor Ortho Biotech Inc. submitted a new drug application to the Food and Drug Administration (FDA) for the use of abiraterone with prednisone to treat mCRPC patients who had previously received taxane-based chemotherapy. An FDA decision is expected by late June.

MDV3100 Uses a Different AR Approach

MDV3100 is a small-molecule AR antagonist that slows tumor growth and induces cell death by blocking testosterone from binding to AR, preventing nuclear translocation, and obstructing recruitment of coactivators. The drug “binds the AR with greater relative affinity than the clinically used antiandrogen bicalutamide,” Dreicer said.

In a phase 1/2 study, MDV3100 demonstrated antitumor effects at all doses for 140 patients with progressive mCRPC who were enrolled in dose-escalation cohorts starting at 30 mg and reaching 600 mg. The cohort consisted of 65 chemotherapy-naïve patients and 75 postchemotherapy patients (J Clin Oncol. 2009;27[suppl 15]: abstract 5011).

In the chemotherapy-naïve group, PSA decreases of ≥50% were reported in 62% of patients, partial or stable soft tissue response was experienced by 38% of patients, and bone disease stabilized in 63%. For the postchemotherapy group, 51% experienced ≥50% PSA decreases, 45% showed partial or stable soft tissue response, and 51% evidenced bone disease stability.

Multiple clinical trials are now underway to study the drug’s efficacy in advanced mCRPC after prior treatment and in earlier-stage disease, according to the joint pharmaceutical developers, Medivation, Inc, and Astellas Pharma Inc.

Other trials are also testing the efficacy of MDV3100. The phase 2 TERRAIN trial, which is seeking to enroll approximately 370 patients, will compare MDV3100 with bicalutamide.

The AFFIRM trial is a phase 3, randomized, double-blind, placebo-controlled trial that has completed enrollment and is evaluating MDV3100 at a 160-mg daily dose versus placebo in 1199 patients. Another phase 3 trial, PREVAIL, is seeking to enroll approximately 1700 men with advanced prostate cancer who have not yet received chemotherapy. They will be randomized to receive either 160 mg daily of MDV3100 plus standard of care versus placebo plus standard of care.