New ASCO/CCO mCRPC Treatment Guideline Incorporates Latest Approved Drugs

Ethan Basch, MD

A guideline for the treatment of men with metastatic castration-resistant prostate cancer (mCRPC) has been issued by the American Society of Clinical Oncology (ASCO) and Cancer Care Ontario (CCO). The guideline is the first released by the groups on the topic of mCRPC since 2007, and incorporates information about 6 recently approved drugs that have significantly changed the therapeutic landscape for these patients.

The guideline recommends indefinite androgen deprivation therapy (ADT), as well as newer systemic therapies that can be given concurrently with that treatment. The document addresses survival, quality-of-life benefits, and side effects for each of these new drugs, and also touches on cost considerations.

“We have seen unprecedented progress against advanced prostate cancer recently, with six new treatments approved in the last couple of years,” said co-chair of the multidisciplinary ASCO/CCO Expert Panel that developed the guideline Ethan Basch, MD, the director of the Cancer Outcomes Research Program at the University of North Carolina Lineberger Comprehensive Cancer Center. “There are a lot of nuances about treatment selection in terms of disease stage and what prior therapies the patient received. We hope this guideline will help doctors and patients make informed treatment decisions.”

The guideline recommends, with moderate strength, that ADT be used indefinitely in these patients. In discussing specific newer drugs to complement ADT, the document strongly recommends abiraterone (given with prednisone), enzalutamide, and radium-223 as treatments that improve survival and quality of life and have a favorable benefit/harm balance. Survival and quality of life are also improved with docetaxel plus prednisone, but a moderate toxicity risk is associated with the treatment; hence, the moderate strength of the recommendation to prescribe it. The guideline gives a weak recommendation to the use of sipuleucel-T in asymptomatic and minimally symptomatic patients, saying it offers improved survival, an unclear effect on quality of life, and low toxicity.

“In the context of incurable metastatic cancer, it is the opinion of the panel that the goal of treatment is to provide the best possible quality of life for as long as possible,” the guideline states. “Over the past decade, multiple therapies have become available for metastatic CRPC that provide overall survival benefit (although generally modest and measured in months), as well as quality of life and pain benefits, demonstrated through well-designed phase III trials. In the contemporary selection of treatments, attention should be given to clinically meaningful benefit, risk of harm, quality of evidence, and cost when assisting patients with treatment decisions.”

Key guideline recommendations state that physicians should:

• Keep patients with mCRPC on ADT (pharmaceutical or surgical) indefinitely. (recommendation level: moderate)
• Offer abiraterone/prednisone, enzalutamide, or radium-223 (for men whose cancer has spread predominantly to the bones) in addition to ADT, as all three treatments are associated with improved survival, quality of life, and favorable balance of benefits and harms. (recommendation level: strong)

• If considering chemotherapy, offer docetaxel/prednisone, but discuss side-effect risks. (recommendation level: moderate)
• If a patient’s disease worsens despite treatment with docetaxel, consider offering cabazitaxel plus prednisone, but discuss side-effect risks. (recommendation level: moderate)
• Consider offering sipuleucel-T to men who have no symptoms or minimal symptoms. (recommendation level: weak)
• Consider offering mitoxantrone plus prednisone, accompanied by a discussion of limited clinical benefit and side-effect risk. (recommendation level: weak)
• Consider offering ketoconazole or antiandrogens (bicalutamide, flutamide, nilutamide), accompanied by a discussion of limited clinical benefit. (recommendation level: weak)
• Consider offering low-dose corticosteroid monotherapy as a second-line hormonal therapy. (recommendation level: weak)
• Offer palliative care early to all patients. (recommendation level: strong)
• Never offer bevacizumab, estramustine, or sunitinib. (recommendation level: strong)

Although insufficient clinical evidence was available to recommend the optimal sequence in which treatments should be given, ongoing clinical trials are exploring this question, as well as potential benefits of combining various treatments.

The guideline builds upon prior recommendations from ASCO and CCO that were based on a systematic review of 28 randomized clinical trials published between 1979 and 2004. Those recommendations were released by CCO in 2006 and endorsed by ASCO in 2007.

An additional 28 randomized clinical trials of systemic therapies for the treatment of mCRPC, including targeted therapies and immunotherapies, have been identified since 2004. These additional randomized trials inform the current recommendations, ASCO stated upon releasing the document.

Other sets of guidelines for the treatment of mCRPC exist, and are mentioned in the ASCO/CCO document.

“Although the recommendations from the NCCN [National Comprehensive Cancer Network], AUA [American Urological Association], and ASCO/CCO guidelines are similar, the ways in which therapies are categorized differ,” the new guideline document states.

“The NCCN guideline separates patients by nonmetastatic versus metastatic and nonsymptomatic versus symptomatic status and further separates symptomatic patients by first- or second-line treatment. The AUA guideline separates patient populations by nonmetastatic versus metastatic status and further divides the metastatic patients by prior docetaxel versus no prior docetaxel, asymptomatic versus symptomatic status, and good versus poor performance status. In contrast, this guideline categorizes and evaluates therapies based on type of clinical benefit (survival and/or quality of life), strength of evidence, and benefit-risk balance. Pertinence of particular therapies to presence of symptoms, bone metastases, or prior treatments is noted at the individual therapy level.”

The ASCO/CCO recommendations, which were compiled via a rigorous, systematic review of literature by experts free of industry-related conflicts of interest, now constitute the most up-to-date guideline for the treatment of mCRPC, said one of its authors, Andrew Loblaw, MD, FRCPC, MSc, professor of Radiation Oncology at Sunnybrook Health Sciences Centre, in Toronto. Loblaw added that the guideline is convenient to use because it offers a table of key recommendations condensed to a page and a half, while also including detailed data for those who are interested.

In a data supplement, Loblaw added, the guideline lists the monthly costs of all the available medications for men with mCRPC, so that doctors and patients can choose the best possible strategies when price is a factor.

While the Medicare rate for a month of treatment with abiraterone is $6409.11, its complementary prednisone—which may offer benefits on its own, Loblaw noted—costs $6.50 a month. Another option is ketoconazole, at a Medicare rate of $19.22 a month.

In addition to being published in the Journal of Clinical Oncology, the new guideline will be incorporated into ASCO’s CancerLinQ, software used by physicians that can respond to their notes about patients by issuing reminders about appropriate treatments, Loblaw said.

“Big Brother won’t be managing everything, but the tools will be there to help remind us to be doing the right thing,” he said. “Eventually, patients will benefit from that.”

The ASCO/CCO guideline is available at http://www.asco.org/guidelines/genitourinary-cancer, along with supplementary materials.

ASCO encourages feedback on its guidelines from oncologists, practitioners and patients through the ASCO Guidelines Wiki at www.asco.org/guidelineswiki.