Impact of Abiraterone Evident in New AUA Guidelines for mCRPC

Adam S. Kibel, MD

Chief, Urologic Surgery

Brigham and Women’s Hospital

Professor of Surgery

Harvard Medical School

Dana-Farber Cancer Institute

Boston, MA

Amid a flurry of new drug approvals in recent years, the American Urological Association (AUA) has issued its first set of guidelines for the management of patients with metastatic castration-resistant prostate cancer (mCRPC). The guidelines, presented during the 2013 AUA Annual Meeting in San Diego, California, in May, incorporate an extensive role for abiraterone acetate (Zytiga) at several stages of the disease.

Abiraterone is part of a class of newer agents called androgen synthesis inhibitors that are designed to target androgen receptors to block the signaling pathways associated with prostate cancer. In 2011, the FDA approved abiraterone in combination with prednisone for patients with mCRPC who had previously received docetaxel. In 2012, that approval was expanded to include patients with mCRPC who have not yet received chemotherapy.

“These trials showed a definitive survival advantage,” said Adam S. Kibel, MD, disease center leader of Urology at Dana-Farber Cancer Institute in Boston, Massachusetts. “Patients didn’t just show a quality of life improvement. Patients lived longer.”

Kibel served as vice chair on a panel for the AUA that developed the guidelines for mCRPC patients. While abiraterone appears to help many patients with mCRPC, the guidelines make it clear that the drug may not be appropriate to use in all cases.

The AUA’s board of directors approved the recommendations in April, before the FDA granted clearance for radium Ra 223 dichloride (Xofigo). As a result, the agent is not mentioned in the guidelines, although it may be in the future, according to a notice attached to the document.

The guidelines discuss treatment options for six different index patients that take into consideration symptoms, performance status, metastases, and whether docetaxel was administered (Table).

Table. Patient Categories for mCRPC Guidelines¹

Index Patient 1—Asymptomatic nonmetastatic CRPC

• Rising prostate-specific antigen (PSA) despite medical or surgical castration
• No radiologic evidence of metastatic prostate cancer
• Castrate levels of testosterone (<50 ng/mL)

Index Patient 2—Asymptomatic or minimally symptomatic mCRPC without prior docetaxel chemotherapy

• Rising PSA in the setting of castrate levels of testosterone
• Documented metastatic disease on radiographic imaging
• No regular narcotics for pain relief for symptoms attributable to metastases

Index Patient 3—Symptomatic mCRPC with good performance status and

no prior docetaxel chemotherapy

• Rising PSA in the setting of castrate levels of testosterone
• Documented symptomatic metastatic disease on radiographic imaging
• Regular narcotics for pain relief for symptoms attributable to metastases

Index Patient 4—Symptomatic mCRPC with poor performance status and

no prior docetaxel chemotherapy

• Performance status Eastern Cooperative Oncology Group (ECOG) 3-4

Index Patient 5—Symptomatic mCRPC with good performance status and prior docetaxel chemotherapy

• Castration-resistant disease based on serologic progression
• Excellent ECOG performance status

Index Patient 6—Symptomatic mCRPC with poor performance status and prior docetaxel chemotherapy

• ECOG performance status 3-4

Two patient indexes for which abiraterone plus prednisone should be offered are for patients who are asymptomatic or minimally symptomatic and have not received prior docetaxel chemotherapy (Index Patient 2), and patients who are symptomatic with good performance status who have received prior docetaxel chemotherapy (Index Patient 5).

For the first setting, Kibel said that while clinical trial data have definitely shown that survival is improved in these patients with abiraterone, it’s not the only choice available.

“The other two treatments, docetaxel and sipuleucel-T [Provenge], also show similar survival advantages, but none of these have been tested head-to-head, so it’s very hard to say which is better,” Kibel said.

In the second setting, cabazitaxel (Jevtana) or enzalutamide (Xtandi) are also options, particularly if the patient already has received abiraterone.

There are two additional groups of patients with mCRPC for whom abiraterone plus prednisone may be appropriate: symptomatic patients with good performance status and no prior chemotherapy (Index Patient 3); and symptomatic patients with poor performance status and no prior docetaxel therapy (Index Patient 4). In both cases, Kibel said that randomized clinical trials have not specifically examined abiraterone in these groups of patients, but it is reasonable to believe that the agent is safe because of the other groups for which abiraterone is approved.

“I think we can extrapolate very reasonably that if it’s been tested in asymptomatic patients pre-docetaxel, it’s been tested in patients after docetaxel, and it’s FDA-approved for patients who have a failure with metastatic disease pre-docetaxel, irrespective of symptomatology, it seems to me that it’s very reasonable to include it in the guidelines,” Kibel said.

However, patients with asymptomatic, nonmetastatic CRPC (Index Patient 1) should not receive treatment with abiraterone. Kibel explained that this patient population really has not been studied in a randomized trial with any therapy, let alone abiraterone. He said guidelines initially recommended observation-only for these patients, but he said the panel realized that some patients would still want some form of treatment.

While some first-generation antiandrogen agents such as bicalutamide and ketoconazole have been studied in some nonrandomized trials, and therefore may be prescribed, abiraterone has not, which is why it is not recommended in this particular setting.

Finally, patients who are symptomatic with poor performance status who have received prior docetaxel chemotherapy (Index Patient 6) are candidates for palliative care. However, the guidelines also say that clinicians may offer treatment with abiraterone plus prednisone, enzalutamide, ketoconazole plus steroid, or radionuclide therapy to selected patients.

“We recognize that some patients really adamantly want some form of treatment, and it’s very hard to say no to patients,” Kibel said. “We thought in selected patients who understood the risks and benefits and really weren’t ready to start using palliative care that it would be reasonable to go ahead and try one of the treatments that had a low side- effect profile, which would include abiraterone but not chemotherapy.”

Kibel said it is important to keep in mind that these are simply guidelines from the AUA, and that, because organizations use different methodologies for developing recommendations, there may not be uniform consensus across all groups about the proper way to manage patients. When it comes to abiraterone, though, Kibel said that its impact is very clear.

“It’s a treatment option that extends life expectancy, which is obviously a very positive thing,” Kibel said. “It’s very well tolerated. And therefore, I think it’s an excellent treatment alternative for patients that are in the appropriate category.”

Reference

1. Cookson MS, Roth BJ, Dahm P, et al. Castration-resistant prostate cancer: AUA guideline. American Urological Association website. http://www.auanet.org/education/guidelines/castration-resistant-prostatecancer.cfm. Published May 6, 2013. Accessed July 1, 2013.