Drugs or Active Surveillance for Low-Risk Prostate Cancer?

In the past, even patients with low-risk prostate cancer would often be treated with surgery or radiotherapy, as men opted for an aggressive approach to get rid of the cancer, despite potentially serious side effects from the treatment.

But recent years have seen a marked move away from immediate treatment. About 60% of patients with low-risk prostate cancer now forgo treatment, opting instead for a regime of active surveillance (AS).

The American Urological Association is urging that the proportion rise still further, to at least 80% in the near future, as emerging research underscores the slow-growing and even nonmalignant nature of most low-risk prostate tumors.

However, some researchers, backed by pharmaceutical companies, appear to be exploring a new treatment approach for these patients.

Rather than advocate only AS for this group, they are looking to the use of oral androgen receptor inhibitors (ARIs), a class of potent and expensive hormonal therapies that include apalutamide, enzalutamide, and darolutamide. So far, these drugs have been approved only for use in the treatment of advanced prostate cancer. Wholesale prices for these drugs exceed $150,000 annually and can reach well into six figures.

The prospect of using medication for patients with less aggressive tumors has alarmed some cancer experts.

Christopher Booth, MD, of the Division of Cancer Care and Epidemiology, Queen’s University Cancer Research Institute, Kingston, Ontario, Canada, said he suspects drug companies may try to cash in on the growing market of patients with early, localized prostate cancer that they previously ignored.

“Uptake of active surveillance over the past two decades has been a huge advance for patients with early-stage prostate cancer, as it allowed us to deescalate care, reduce side effects, and preserve good outcomes,” Booth told Medscape Medical News.

I cannot see how this represents an important advance for patients. I worry we are taking a step backward if clinicians begin to adopt this approach over true active surveillance.
Dr Christopher Booth

Regarding the prescribing of ARIs to men who don’t need them, Booth said, “I cannot see how this represents an important advance for patients. I worry we are taking a step backward if clinicians begin to adopt this approach over true active surveillance.”

Channing Paller, MD, a medical oncologist at Johns Hopkins University, Baltimore, said she doesn’t think she’d ever recommend hormonal therapy to any patient with low- or favorable intermediate–risk prostate cancer.

“I think the patient will likely do well anyway and still has options for therapy if there is clinical progression,” Paller said. “I am concerned about adding in hormonal therapy, even oral agents, because it just gives individuals side effects for not clinically significant endpoints.”

Several recent studies have explored the use of hormonal therapy for men with low- to intermediate-risk prostate tumors. In June, for example, JAMA Oncology published findings from the ENACT trial, which compared the ARI enzalutamide to AS in 227 men with low- to intermediate-risk prostate cancer.

The trial launched in 2016, before AS flourished as an approach to managing the disease in the United States.

At face value, the study was a success. Compared with AS alone, the drug reduced the risk of pathologic or therapeutic progression of prostate cancer by 46%.

However, the drug ― which crosses the blood-brain barrier ― was associated with significant side effects, including decreases in energy and libido, a gain in visceral abdominal weight, and the possibility of worsening cardiovascular risks or complications, depression, bone demineralization, and hot flashes. Neal Shore, MD, principal investigator of ENACT and medical director for the Carolina Urologic Research Center, Myrtle Beach, South Carolina, said not all patients want to go on AS, which can lead to cancer anxiety and has a large dropout rate. About 30% of men on AS discontinue the approach within 5 years because their cancer progresses, and some urologists urge patients who have high-volume, low-risk prostate cancer to be treated immediately.

Michael Schweizer, MD, a medical oncologist at the University of Washington in Seattle, conducted a 2020 pilot study that showed that apalutamide, another ARI, can suppress cancer in men who otherwise would qualify for AS.

“I think drug companies would love to tap into the ‘active surveillance market.’ The challenge is that there’s no clear pathway to getting FDA approval in this setting, as clinical trial endpoints have not been validated,” Schweizer said. “I think medications could become part of routine management of men on AS, but we need better ways to identify patients who need treatment.” Such patients include those who would need surgery or radiotherapy in the absence of treatment.

So far, drugmakers say they have no interest in pursuing ARIs for low-risk cancers.

A spokesperson for Astellas, which collaborated with Pfizer Oncology on the ENACT trial, said the company has no plans for additional research on early-stage prostate cancer and has no plans to submit ENACT data to global regulatory agencies.

A spokesperson for Bayer Healthcare, the manufacturer of darolutamide, which does not cross the blood-brain barrier, said the company is not sponsoring any of its own investigations of its drug in low- or intermediate-risk localized prostate cancer. But Bayer is supporting an independently conducted trial at Dana-Farber Cancer Institute, Boston, of intermediate-risk localized prostate cancer.

A different way of delivering drugs that minimizes toxicity could encourage use of ARIs.

Pamela Munster, MD, is a medical oncologist at the University of California, San Francisco, and founder of Alessa Therapeutics. The company has been developing Biolen, silicon-based implantable seeds that release medication directly into the prostate. She is conducting two proof-of-concept studies to determine whether locally delivered medications can prevent side effects from ARIs.

William Catalona, MD, a pioneering urologic surgeon at Northwestern University Feinberg School of Medicine, said ARIs may have a future for patients with low-risk to intermediate-risk disease who otherwise would opt for AS or focal therapy.

“Of course, any form of [ARI] would be expected to slow the progression of prostate cancer, and favorable intermediate-risk disease does progress more frequently and more rapidly, so it does deserve consideration,” Catalona said.But what are the literal and virtual costs?”

Most of his patients taking enzalutamide “don’t feel well,” he said. “Many suffer from extreme fatigue, and some refuse to continue taking this medication. Gynecomastia is also problematic to most men.”

Although other drugs might delay progression with fewer side effects, “most active surveillance patients are strongly motivated to avoid potential adverse side effects associated with treating prostate cancer,” Catalona said.

The ultimate arbiter, he added, will be level-1 evidence from prospective, randomized trials conducted by well-known investigators and published in prestigious journals. “Stay tuned,” he said.

Munster is founder of and owns shares in Alessa Therapeutics. Schweizer has received research funding from Janssen Pharmaceuticals. Shore received personal fees from Astellas and Pfizer during the conduct of the study as well as personal fees from Bayer, AstraZeneca, Janssen, Dendreon, Sanofi, Myovant, and Merck. Booth, Catalona, and Paller report no relevant financial relationships.

Howard Wolinsky is a Chicago-based medical journalist. You can read more of his stories about prostate cancer at TheActiveSurveillor.com.

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