The ASCO Clinical Practice Guidelines Committee and the Cancer Care Ontario (CCO) program in evidence-based care have released a clinical practice guideline on systemic therapy in men with metastatic castration-resistant prostate cancer. The guideline was published in the Journal of Clinical Oncology.¹

The guideline is the result of efforts of a multidisciplinary ASCO/CCO expert panel, which developed evidence-based recommendations through a systematic review of the literature guided by the question: “Which systemic therapies improve outcomes in men with metastatic [castration-resistant prostate cancer]?” The evidentiary basis of the guideline consists of 26 randomized controlled ­trials identified through a 2012 CCO systematic review² and an updated literature search through June 2014.

The panel was chaired by Ethan Basch, MD, MSc, Director of the Cancer Outcomes Research Program and Associate Professor of Medicine and Public Health at the Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill.

In Brief

In brief, the guideline recommends that androgen deprivation be continued indefinitely. Systemic therapy that should be offered includes abiraterone acetate (Zytiga)/prednisone, enzalutamide (Xtandi), and radium-223 (Xofigo) for men with predominantly bone metastases, with docetaxel/prednisone also being offered accompanied by discussion of toxicity risk. Sipuleucel-T (Provenge) may be offered to asymptomatic/minimally symptomatic men, with an understanding that quality-of-life outcomes data are not available. Cabazitaxel (Jevtana) may be offered to patients experiencing disease progression on docetaxel, with an understanding that quality-of-life benefits are not shown and high levels of toxicities have been reported.

Mitoxantrone can be offered accompanied by discussion of limited clinical benefit and toxicity risk, and ketoconazole or antiandrogens (eg, bicalutamide, flutamide, and nilutamide [Nilandron]) may be offered, accompanied by discussion of unknown clinical benefit amidst known toxicities. Bevacizumab (Avastin), estramustine (Emcyt), and sunitinib (Sutent) should not be used.

There is insufficient evidence to identify optimal sequences or combinations of therapies. Palliative care should be offered to all patients.

Individual recommendations are summarized below.

Androgen-Deprivation Therapy

• Continuous androgen deprivation (pharmaceutical or surgical) should be continued indefinitely regardless of additional therapies (benefit = moderate; harm = moderate; evidence strength = weak; recommendation strength = moderate).

Therapies in Addition to Androgen-Deprivation Therapy

Therapy with survival and quality-of-life benefits

• Abiraterone acetate and prednisone (benefit = moderate; harm = low; evidence strength = strong; recommendation strength = strong).
• Enzalutamide (benefit = moderate; harm = low; evidence strength = strong; recommendation strength = strong).
• Radium-223 should be offered to men with bone metastases (benefit = moderate; harm = low; evidence quality = strong; recommendation strength = strong).
• Docetaxel and prednisone (benefit = moderate; harm = moderate; evidence strength = strong; recommendation strength = moderate). Recent data suggest a substantial survival benefit with addition of a limited course of docetaxel to androgen-deprivation therapy in newly diagnosed metastatic androgen-sensitive prostate cancer, primarily in patients with high burden of metastatic disease (ie, visceral disease or more than four bone metastatic lesions). The additive benefits or toxicities associated with subsequent docetaxel retreatment of such patients in the castration-resistant setting are unknown.

Therapy with survival benefit and unclear quality-of-life benefit

• Sipuleucel-T may be offered to asymptomatic or minimally symptomatic men (benefit = moderate; harm = low; evidence strength = moderate; recommendation strength = weak).
• Cabazitaxel and prednisone may be offered to patients with disease progression on docetaxel (benefit = moderate; harm = moderate to high; evidence strength = strong; recommendation strength = moderate).

Therapy with quality-of-life benefit without demonstrated survival benefit

• Mitoxantrone plus prednisone (benefit = low; harm = high; evidence strength = weak; recommendation strength = weak).

Therapy with biologic activity and unknown survival or quality-of-life benefit

• Antiandrogens—eg, bicalutamide, flutamide, and nilutamide (benefit = low; harm = low; evidence strength = weak; recommendation strength = weak).
• Ketoconazole (benefit = low; harm = moderate; evidence strength = weak; recommendation strength = weak).
• Low-dose corticosteroid monotherapy (benefit = low; harm = low; evidence strength = weak; recommendation strength = weak).

Therapy with no demonstrated survival or quality-of-life benefit

• Bevacizumab, estramustine, and sunitinib should not be offered (for each: benefit = none; harm = high; evidence strength = moderate; recommendation strength = strong).

Palliative Care Services

• Palliative care should be offered to all patients, particularly to those exhibiting symptoms or quality-of-life decreases, regardless of treatment type (benefit = moderate; harm = none; evidence strength = moderate; recommendation strength = strong).

Qualifying Statements

• Clinicians should review the published regimens discussed in the guideline for use in appropriate patient populations and for dose selections/modifications.
• There is insufficient published evidence to recommend specific sequencing or combinations of recommended therapies (except as otherwise noted in full guideline).
• A distinction made in some clinical trials between pre- and post-docetaxel treatment contexts should not play a role in selecting therapies for individual patients (unless otherwise noted).
• Patients may place a higher importance on quality of life than length of life. Treatment decisions require understanding of individual patient values and preferences. Many patients with incurable metastatic disease believe the goals of care to be curative; clear communication about goals and potential benefits and harms of care is necessary.
• Cost and availability may influence treatment decisions, and these factors must be discussed with patients.
• Most phase III clinical trials have included patients with good baseline performance status. Choices of treatment for patients with diminished performance status are not clearly established by existing evidence in most cases. ■

Disclosure: For full disclosures of the guideline authors, visit jco.ascopubs.org.

References

1. Basch E, Loblaw DA, Oliver, TK, et al: Systemic therapy in men with metastatic castration-resistant prostate cancer: American Society of Clinical Oncology and Cancer Care Ontario Clinical Practice Guideline. J Clin Oncol. September 8, 2014 (early release online).

2. Loblaw DA, Walker-Dilks C, Winquist E, et al: Systemic therapy in men with metastatic castration-resistant prostate cancer: A systematic review. Clin Oncol (R Coll Radiol) 25:406-430, 2013.

See commentary by Maha Hussain, MD, FACP, here.