AUA Offers Evidence-Based Guide For Sequencing CRPC Therapies

Michael Cookson, MD

Patients with castration-resistant prostate cancer (CRPC) should receive treatment supported by the best evidence for specific disease characteristics, according to a clinical guideline developed by the American Urological Association (AUA).

The guideline, the AUA’s first for the treatment of CRPC, outlines a course of action based on six “index patients,” ranging from men with asymptomatic, nonmetastatic CRPC to those with symptomatic, metastatic disease, poor performance status, and previous exposure to docetaxel chemotherapy. The guideline was presented today during the AUA’s 2013 Annual Meeting in San Diego, California.

“The timing was right for a guideline, because there is a lot going on in the field of prostate cancer, including the recent approval of four new therapies for castration-resistant prostate cancer and the hope that more new agents are coming,” said guideline committee chair Michael Cookson, MD, of Vanderbilt University in Nashville, Tennessee.

“When you have a lot of management or treatment options that are extending the life and improving the quality of life of these patients, it’s confusing for practitioners in terms of when to use them, knowing when the agents are appropriate,” Cookson continued. “In developing this guideline, we hoped to cast a net, look into what’s available, and then put the information into a user-friendly clinical algorithm for practicing physicians.”

Historically, men with metastatic CRPC (mCRPC) have had a median survival of less than 2 years. However, the approval of four new agents in a span of less than 3 years has helped improve survival, even though mCRPC remains an incurable disease, Cookson said in his introduction to the guideline at the AUA meeting.

“While greater availability of effective agents benefits patients, multiple options and sequencing may complicate decision making,” he said.

Following an extensive literature review that extended to February 2013, members of the guideline-writing committee assembled a clinical algorithm that recommended certain therapies at different stages of the disease. The authors organized the information and recommendations according to the applicability of therapies to six types of patients.

The index patients and their guideline therapies are based on presence or absence of metastatic disease, degree and severity of symptoms, performance status, and prior docetaxel therapy. The clinical document also addresses protection and preservation of bone health in all six types of patients.

Index patient 1 has asymptomatic, nonmetastatic CRPC, for which the AUA recommends observation with continued androgen deprivation therapy. Physicians may offer first-generation antiandrogens or androgen synthesis inhibitors to selected patients who are unwilling to accept observation. Physicians should not offer systemic chemotherapy or immunotherapy, except within the context of a clinical trial.

Index patient 2 has asymptomatic or minimally symptomatic mCRPC and no history of exposure to docetaxel. For this patient, treating physicians should offer abiraterone + prednisone, docetaxel, or sipuleucel-T, assuming the patient has good ECOG performance status. Because the agents have not been compared directly in head-to-head clinical trials, sequencing should be guided by toxicity profile, beginning with the least toxic agent, according to the AUA.

Patients who do not want or cannot be treated with a standard therapy can be offered first-generation antiandrogen therapy, assuming they have good performance status.

Index patient 3 has symptomatic mCRPC, good performance status, and no prior exposure to docetaxel. According to the guideline, clinicians should first offer docetaxel to these patients, if they have good performance status. Alternatively, clinicians may offer abiraterone + prednisone. If such a patient does not want or cannot be treated with standard therapies, clinicians may offer ketoconazole + steroid, mitoxantrone, or radionuclide therapy. According to the AUA, physicians should not offer estramustine or sipuleucel-T to patients who meet index 3 criteria.

Index 4 patients have symptomatic mCRPC and no prior treatment with docetaxel but have poor performance status. The AUA advises clinicians that they may offer abiraterone + prednisone to these patients or, if the patients refuse or are unable to receive that course of treatment, ketoconazole + steroid or radionuclide therapy.

In select index 4 patients whose performance status is directly related to the cancer, clinicians may offer docetaxel or mitoxantrone but should not offer sipuleucel-T.

Index patient 5 has symptomatic mCRPC, good performance status, and a history of treatment with docetaxel. For these patients, clinicians should offer abiraterone + prednisone, cabazitaxel, or enzalutamide. In select patients who received abiraterone before docetaxel, clinicians should offer cabazitaxel or enzalutamide.

In situations wherein abiraterone, cabazitaxel, or enzalutamide are unavailable, ketoconazole + steroid may be offered. Index 5 patients might also be offered retreatment with docetaxel if they discontinued because of reversible side effects and were benefiting from the agent at the time of discontinuation.

Index patient 6 has symptomatic mCRPC, poor performance status, and prior docetaxel treatment. These patients should be offered palliative care, or, alternatively for selected patients, abiraterone + prednisone, enzalutamide, ketoconazole + steroid, or radionuclide therapy.

“Of course there is flexibility in the guideline, but clinicians should recognize that the level of evidence dictates the statements and recommendations we can make,” said Cookson. “The AUA has set the bar high in terms of supporting evidence, and we followed the criteria to ensure that clinicians get the most evidence-based information possible.”

The AUA recommends that clinicians address bone health for all patients, regardless of index status. Clinicians should offer preventive therapy for fractures and skeletal-related events (SREs). For patients with bony metastases, treating physicians may offer denosumab or zoledronic acid for prevention of SREs.

“Although our primary objective was treatment of the disease and true survival benefit, bone health is important to all patients with castration-resistant prostate cancer,” said Cookson. “We recognized this and addressed it in the guideline.”

Cookson MS, Roth BJ, Dahm P, et al. Castration-Resistant Prostate Cancer: AUA Guideline. Presented at the American Urological Association Annual Meeting; May 4-8, 2013; San Diego, California.

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