New Focus on ADT in Prostate Cancer Guideline

For the first time in its long and storied history, hormonal therapy for advanced prostate cancer has received broad and detailed attention in a clinical practice guideline.

The new American Urological Association (AUA) guideline provides direction for the use of hormonal therapy (or androgen-deprivation therapy, ADT) for men with multiple categories of advanced and metastatic prostate cancer.

“[ADT] is a mainstay of management that we’ve known about since the Nobel Prize-winning work in the 1940s,” said guideline co-chair Michael Cookson, MD, of the University of Oklahoma Health Sciences Center in Oklahoma City. “It’s taken a long time to get there, and that’s partly due to the fact that a lot of what we did was empiric. There weren’t many trials designed to show the true benefit.”

Another guideline first reflects the growing recognition of the different stages of disease evolution before the emergence of metastatic castration-resistant prostate cancer (mCRPC).

“There’s a lot of excitement in the field about newly diagnosed metastatic disease,” Cookson told MedPage Today. “Most of the early trials were in men who failed hormonal therapy. Now the trials have moved back to earlier in the disease, looking at conventional hormonal therapy, plus. That ‘plus’ initially included chemotherapy, which showed survival advantages of 12 to 18 months. That was big.

“Then additional androgen-active therapies, such as abiraterone (Zytiga) and then oral agents such as enzalutamide (Xtandi) and now apalutamide (Erleada). That translated into a year or more of additional cancer control and survival when the disease was treated earlier with the combination,” he said.

The guideline also addressed the evolutionary period before emergence of radiographically confirmed mCRPC, often associated with a rapid rise in prostate-specific antigen (PSA). Now known as nonmetastatic CRPC, the disease state has three FDA-approved options in the androgen receptor antagonist drug class: darolutamide (Nubeqa), in addition to enzalutamide and apalutamide. The drugs’ approval was based primarily on the newly recognized endpoint of metastasis-free survival and relatively limited overall survival data, said Cookson. Subsequently, a survival advantage was reported for enzalutamide.

“That’s been a real area of controversy,” he continued. “Many clinicians were hesitant to fully embrace the therapy because they didn’t really understand the true benefit of this new endpoint called metastasis-free survival. The ‘purists’ among oncologists, and maybe just the purists in general, want an overall survival benefit. Now we’re starting to see that happen. There are three studies in that category, and as the data matures, I think we’ll see more of that, since the drugs are pretty similar.”

Frontline standard of care for mCRPC remains docetaxel for men with no prior exposure to the drug. Cabazitaxel (Jevtana) or a novel anti-androgen agent is appropriate in the setting of docetaxel failure.

New to guideline history — and to many clinicians who treat prostate cancer — is genetic testing. About a fourth of CRPC harbors germline or somatic mutations, said Cookson. New drugs that target the mutations continue to emerge on a regular basis, affording opportunities for precision-medicine approaches to treatment of CRPC. The most common mutation is BRCA2, and the FDA has already approved two drugs to treat CRPC harboring BRCA2 mutations, the PARP inhibitors olaparib (Lynparza) and rucaparib (Rubraca).

“There are instances in which men have been on conventional therapy — chemotherapy or hormonal therapy — and they’ve also failed the newer antiandrogens, such as abiraterone and enzalutamide,” said Cookson. “In the past, we didn’t have much hope for them. Now there is a class of drugs that if they have the right genetic makeup in their tumor, they’re going to have a better chance to respond to the therapy.”

Immunotherapy may also have a role for some men with CRPC. The PD-1 inhibitor pembrolizumab (Keytruda) has tumor-agnostic approval for treatment of heavily mutated solid tumors (microsatellite instability-high). The field of prostate cancer is “still in its infancy” with regard to use of drugs that target genetic alterations in tumors.

The key message in the guideline is for prostate cancer specialists to be aware of recommendations for genetic testing, particularly for men with aggressive disease that progresses rapidly through conventional therapies, Cookson added. Moreover, testing for germline mutations has implications for genetic counseling, including family members who might be at increased risk for several types of cancer.

The guideline was developed in collaboration with the Society of Urologic Oncology and the American Society for Radiation Oncology. The guideline panel made a total of 38 recommendations pertaining to the the prostate cancer continuum of care:

• Early evaluation and counseling

• Nonmetastatic biochemical recurrence after exhaustion of local treatment options

• Metastatic hormone-sensitive prostate cancer

• Nonmetastatic CRPC

• Bone health

The complete guideline is available on the AUA website. Cookson and the other guideline co-chair, William Lowrance, MD, of the University of Utah School of Medicine and the Huntsman Cancer Institute in Salt Lake City, summarized the key points of the guideline during the AUA virtual meeting.

“For the past several years, the prostate cancer landscape has been rapidly evolving due to changes in PSA screening standards, as well as the approval of new classes of treatment options for use in various prostate cancer disease states,” Lowrance said in a statement. “This guideline is comprised of clinical recommendations based on this new evidence and aims to further support the medical community and patients as they navigate through the various stages of this disease.”