Pharmaceutical or surgical androgen deprivation should be continued indefinitely in men with metastatic castration-resistant prostate cancer, and abiraterone acetate/prednisone, enzalutamide, or radium-223 should also be offered, according to updated guidelines published online Sept. 8 in the Journal of Clinical Oncology.

The question posed to the panel of experts convened by the American Society of Clinical Oncology and Cancer Care Ontario (CCO) was simple: Which systemic therapies improve outcomes in men with metastatic castration-resistant prostate cancer? The effort builds on previous recommendations from both groups (BMC Cancer 2006;6:112 and Clin. Oncol. [R. Coll. Radiol.] 2013; 25:406-30).

"For men with androgen-sensitive metastatic disease, continuous androgen-deprivation therapy is the current standard of care," wrote the panel of authors led by Dr. Ethan Basch of University of North Carolina, Chapel Hill. "Ultimately, many of these men will develop castration-resistant prostate cancer (CRPC), warranting additional lines of therapy added to androgen-deprivation therapy."

The panel conducted a systematic review of medical literature published through June 2014 to search for trials that could inform recommendations. Studies were included if they were randomized, controlled trials or summaries based on such trials; if they included men with metastatic CRPC; if they compared systemic therapy, alone or in combination with other agents, versus placebo or other drug regimens; and if they were published English-language reports.

The researchers excluded articles if they involved only androgen-deprivation therapy, bone targeted agents, or radionuclides. Trials were required to have at least 50 patients per study arm, and in mixed study populations at least 90% of men were required to have metastases.

Based on analysis of 26 randomized, controlled trials, the panel determined that when added to androgen deprivation, three treatments demonstrated strong evidence of survival as well as QOL benefit, with a favorable benefit-risk profile: abiraterone acetate, enzalutamide, and radium-223 (for patients with predominantly bone metastases). "The toxicity profile of radium-223 is favorable when historically compared with other radiopharmaceuticals used in this population," the panel wrote.

"It is not known whether combining radium-223 with other treatments improves clinical outcomes. Radium-223 should be considered for patients with bone disease, whereas abiraterone or enzalutamide should be considered for those with bone and/or soft tissue disease. Use of any of these agents in combination should be restricted to the context of prospective clinical trials," they said (J. Clin. Oncol. 2014 Sept. 8 [doi:10.1200/jco.2013.54.8404]).

The panel also found that docetaxel with prednisone remains an acceptable therapy to offer patients based on strong evidence of improved survival, pain, and overall QOL, "but it has a relatively higher risk of toxicity when compared historically with abiraterone, enzalutamide, or radium-223. Potential harms of this therapy should be discussed with patients at the time of decision making in relation to the apparently lower risk of harms associated with other options and to the patient’s individual circumstances. If administered, docetaxel should be given every 3 weeks, which has been shown to be superior to a once-per-week schedule."

For men who are asymptomatic or mildly asymptomatic, sipuleucel-T "remains an option" as risks of harm are "relatively low," though impact on QOL has not been formally studied.

For men who have previously received docetaxel, cabazitaxel with prednisone offers a statistically significant overall survival benefit, "although it does not seem to substantially improve pain; impact on QOL is not known, but it carries a substantial toxicity profile," the panel wrote. A high toxicity risk is associated with the use of mitoxanthrone after docetaxel. No survival benefit has been observed with this agent, but it "may be commercially available where others are not and is generally less costly."

Clinical trials of several products have been conducted in men with CRPC without evidence of overall benefit in clinically meaningful patient outcomes, including atrasentan, bevacizumab, calcitriol, GVAX, orteronel, satraplatin, sunitinib, and zibotentan. "Products have been tested alone or in addition to docetaxel," the panel wrote. "Of these, bevacizumab and sunitinib have been approved by regulatory authorities for other indications."

The panel emphasized that patients "should be fully informed about the extent of potential benefit as well as harm and cost of treatment before making decisions. ASCO and CCO consider it essential to good clinical practice to [ensure] that this information and the goals of care are understood. Many patients misunderstand the goals of care in the setting of metastatic disease to be curative rather than palliative. This may lead to decisions to accept excess toxicity or cost based on incorrect assumptions about potential benefit. Palliative care should be offered to all patients, particularly to those exhibiting symptoms or QOL decrements," the panel said.

Members of the panel reported consultancy or advisory roles and funding from numerous pharmaceutical companies.

dbrunk@frontlinemedcom.com

On Twitter @dougbrunk

Androgen deprivation should be continued indefinitely in men with metastatic castration-resistant prostate cancer