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Targeting the Androgen Receptor in Castrate-resistant Prostate Cancer: A Step Forward

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 4th European Multidisciplinary Meeting on Urological Cancers (EMUC 2012)

Barcelona, Spain / November 16-18, 2012

Barcelona - In prostate cancer, medical or surgical androgen ablation therapy leads to tumour regression and a rapid decline in prostate-specific antigen (PSA). However, progression of the cancer despite castrate levels of testosterone is a signal that the disease has evolved to a castration-resistant prostate cancer (CRPC) phenotype, against which traditional hormonal therapies have little effect. Novel agents target the androgen receptor, either by blocking androgen production from multiple sources including the testes, the adrenal glands and even the prostate tumour itself or by directly inhibiting the androgen-receptor signalling pathway. Results from studies confirm that the newer agents extend survival and improve clinical outcomes of patients with metastatic CRPC.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

A better understanding of the molecular underpinnings that drive prostate cancer to become resistant to endocrine therapy is opening up a new era of targeted therapies. “Castrate-resistant prostate cancer (CRPC) is an androgen receptor-driven disease but the mechanisms leading to CRPC are diverse,” Prof. Jack Schalken, Radboud University Nijmegen Medical Centre, the Netherlands, told delegates. For example, studies indicate that even castrate levels of androgen can activate the androgen receptor and prolong cancer cell survival.

The adrenal glands represent one source of these androgens, Dr. Schalken noted, but the prostate cancer itself can fuel cancer cell growth. Experimental evidence suggests a number of mechanisms, including synthesis of androgens directly in prostate cancer cells due to an upregulation of enzymes, lead to continuous activation of androgenic receptors; this and the overexpression of androgen receptors have been identified in the progression of prostate cancer.

Given the role of the androgen receptor in CRPC, therapies that offer either more complete androgen deprivation or that inhibit the androgen-receptor signalling pathway hold promise as therapeutic alternatives for men with CRPC.

Multi-Step Inhibition

As described by Prof. Peter Mulders, Radboud University Nijmegen Medical Centre, enzalutamide targets multiple steps in the androgen-receptor signalling pathway. First, it prevents androgens from binding to the androgen receptor. It also impairs nuclear translocation of the androgen receptor and inhibits androgen receptor-mediated DNA binding and coactivator recruitment. Collectively, these actions prevent further transcription, resulting in tumour cell death.

The efficacy of enzalutamide in metastatic CRPC (mCRPC) was demonstrated in the recently published AFFIRM trial (N Engl J Med 2012;367:1187-97). When AFFIRM was initiated, no life-prolonging treatment was available for men with progressive prostate cancer after standard of care docetaxel chemotherapy.

In his review of AFFIRM, Prof. Mulders described the patient population which included a total of 1199 men with progressive CRPC who had previously received docetaxel chemotherapy for treatment of metastatic disease. Eight hundred patients were randomized to oral enzalutamide 160 mg once-daily and 399 were randomized to placebo. Of note, enzalutamide is given without the need for concomitant prednisone, unlike some of the newer targeted therapies. The primary end point was overall survival (OS).

At the time of the interim analysis, the median time on treatment was 8.3 months in the active drug arm and 3 months for placebo patients. Prof. Mulders observed that with a median survival of 18.4 months for enzalutamide vs. 13.6 months for placebo, it prolonged survival by a median of 4.8 months—a 37% reduction in the risk of death compared with placebo (HR 0.63; P<0.001). On the basis of these results, the data safety monitoring committee recommended the study be halted and eligible patients in the placebo group were offered active therapy.

Time to first skeletal-related event (SRE) was improved by 31% with enzalutamide (16.7 months) compared with placebo (13.3 months; P<0.001). SREs were defined as radiation therapy or surgery to bone, pathologic bone fracture, spinal cord compression or change in antineoplastic therapy to treat bone pain.

Men randomized to the active therapy arm had a high PSA response rate as well, with over half of them achieving >50% decline in PSA levels. Time to PSA progression was also significantly longer for men in the active therapy arm at 8.3 months compared to 3 months for the placebo arm (P<0.001).

Prof. Mulders reviewed data as presented at ESMO 2012 this year (Abstract 8960). Findings showed that pain palliation—defined as a 30% reduction in baseline pain score without a 30% increase in analgesic use at week 13—was achieved in 45% of patients on enzalutamide compared with only 7% of placebo patients (P=0.0079). “If you can influence pain with a drug like enzalutamide, it really benefits the patient,” Prof. Mulders observed.

Supporting this improvement in pain were other quality-of-life responses as measured by the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire. Across every domain measured, enzalutamide significantly improved physical, social, emotional and functional well being compared with placebo. There were also few differences in the side effect profile between active drug and placebo.

“If you treat a patient with enzalutamide without prednisone, the side effect profile is very good and even in the post-chemotherapy setting, its effectiveness is substantial,” Prof. Mulders stated.

Androgen Biosynthesis Inhibition: Another Option

Another important advance in the treatment of CRPC was demonstrated with abiraterone acetate, a highly selective inhibitor of androgen biosynthesis that blocks cytochrome P450 c17 (CYP 17), a critical enzyme in testosterone synthesis. By blocking androgen synthesis in the testes, the adrenal glands and within the prostate tumour itself, it leads to profound androgen depletion. Dr. Joaquim Bellmunt, University Hospital del Mar, Barcelona, Spain, reviewed the phase III COU-AA-301 trial, and the COU-AA-302 study that had been previously reported at ASCO this year.

In COU-AA-301, 1195 patients with mCRPC previously treated with docetaxel were randomized to prednisone
5 mg b.i.d. plus abiraterone 1000 mg/day or placebo. The primary end point was OS. Median OS results at a median follow-up of 20.2 months were 15.8 months with abiraterone vs. 11.2 months for placebo—a 26% reduction in the risk of death with active therapy (HR 0.74; P<0.0001). Median time to PSA progression was 8.5 months and 6.6 months and the median radiographic progression-free survival (rPFS) was 5.6 months vs. 3.6 months for abiraterone and placebo, respectively (both P<0.0001). The proportion of patients who achieved a PSA response was 29.5% and 5.5% respectively, (P<0.0001).

COU-AA-301 thus confirmed that abiraterone acetate significantly prolongs OS in patients with mCRPC following docetaxel chemotherapy with a tolerable adverse event profile.

At ASCO this year, Ryan et al. reported interim results of the COU-AA-302 study in which abiraterone plus prednisone was compared to placebo and prednisone in chemo-naive, asymptomatic or mildly symptomatic mCRPC patients. The interim analysis for the COU-AA-302 study showed that abiraterone plus prednisone produced a statistically significant improvement in rPFS and a strong trend for increased OS. Abiraterone resulted in clinically and statistically significant effects on all secondary end points with an acceptable tolerability/safety profile. 

As reviewed by Dr. Bellmunt, median OS in COU-AA-302 has not yet been reached in the abiraterone arm vs. 27.2 months in the placebo arm (P=0.0097). The median rPFS (8.3 months in the placebo arm; P<0.0001) and the median time to opiate use for cancer-related pain (23.7 months for placebo; P=0.0001) have not yet been reached either.

Time to chemotherapy initiation at 25.2 months vs. 16.8 months; time to ECOG Performance Status deterioration at 12.3 months vs. 10.9 months and time to PSA progression at 11.1 months vs. 5.6 months for abiraterone and placebo, respectively, were all statistically significant in favour of abiraterone.

Abiraterone acetate plus prednisone is currently approved for use in patients with CRPC previously treated with docetaxel.

Summary

The ability of prostate cancer cells to adapt to an environment of androgen deprivation has long been recognized but the ability to capitalize on the molecular pathways that give rise to CRPC is only now being realized. With the arrival of novel agents that can induce potent androgen depletion or which directly target the androgen-receptor signalling pathway, multiple opportunities for improved disease control will soon be part of a new therapeutic armamentarium that can extend survival and improve quality of life for those with progressive metastatic disease. 

Medical Education Network (Mednet) reports which have been accredited by McGill University under the MedPoint Accredited Conference Report Series are eligible for Mainpro-M1 and MOC Program credits.

© 2012 Medical Education Network Canada Inc. All rights reserved. Priority Press™ is an independent medical news reporting service providing educational updates reflecting peer opinion from accredited scientific medical meetings worldwide and/or published peer-reviewed medical literature. Distribution of this educational publication is made possible through the support of industry under written agreement that ensures independence. Views expressed are those of the participants and do not necessarily reflect those of the publisher, McGill University or the sponsor. No claims or endorsements are made for any products, uses or doses. Specific medicines or treatment strategies discussed in this publication may not yet be approved in Canada. Prior to prescribing any medication, the complete prescribing information in Canada, including indications, contraindications, warnings, precautions, and adverse effects should be consulted. No part of this publication may be reproduced in any form or distributed without written consent of the publisher. Information provided herein is not intended to serve as the sole basis for individual care. Our objective is to facilitate physicians’ and allied health care providers’ understanding of current trends in medicine. Your comments are encouraged.

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