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Drugs or Active Surveillance for Low-Risk Prostate Cancer?

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In the past, even low-risk prostate cancer patients were often treated with surgery or radiation therapy, as men took an aggressive approach to getting rid of cancer despite the potentially serious side effects of treatment.

But in recent years there has been a marked shift away from immediate treatment. Approximately 60% of patients with low-risk prostate cancer currently refuse treatment, opting for active surveillance (AS) instead.

The American Urological Association is pushing for this proportion to rise even further, to at least 80% in the near future, as new research highlights the slow growth and even noncancerous nature of most low-risk prostate tumors.

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However, some researchers, supported by pharmaceutical companies, seem to be exploring a new approach to treating these patients.

Instead of advocating only AS for this group, they are considering the use of oral androgen receptor inhibitors (ARIs), a class of potent and expensive hormonal drugs that include apalutamide, enzalutamide, and darolutamide. So far, these drugs have only been approved for use in the treatment of advanced prostate cancer. Wholesale prices for these drugs exceed $150,000 per year and can reach six figures.

The prospect of using drugs for patients with less aggressive tumors has alarmed some cancer specialists.

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Christopher Booth, MD, from the Department of Cancer Treatment and Epidemiology at the Institute for Cancer Research at Queen’s University, Kingston, Ontario, Canada, said he suspects pharmaceutical companies may be trying to cash in on the growing market for patients with early, localized prostate cancer. previously ignored.

“The introduction of active surveillance over the past two decades has been a huge advancement for patients with early stage prostate cancer, as it has allowed us to reduce treatment, reduce side effects, and maintain good outcomes,” Booth told Medscape Medical News.

I don’t see how this represents an important advance for patients. I worry that we will take a step back if clinicians start using this approach instead of true active surveillance.
Dr. Christopher Booth

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Regarding giving RRIs to men who don’t need them, Booth said: “I don’t see how this represents an important advance for patients. I worry that we are taking a step back if clinicians start using this approach instead of true active surveillance. “

Channing Paller, MD, an oncologist at Johns Hopkins University in Baltimore, said she doesn’t think she would ever recommend hormone therapy to any patient with low- or favorable-moderate-risk prostate cancer.

“I think the patient is likely to recover anyway and still have treatment options if there is clinical progression,” Paller said. “I’m concerned about adding hormone therapy, even oral medications, because it just gives people side effects for clinically non-significant endpoints.”

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Several recent studies have examined the use of hormone therapy in men with low- and intermediate-risk prostate tumors. For example, in June, JAMA Oncology published the results of the ENACT study, which compared ARI enzalutamide with AS in 227 men with low- and intermediate-risk prostate cancer.

The trial began in 2016, before AS had blossomed as a treatment approach for the disease in the United States.

At first glance, the study was successful. Compared with AS monotherapy, the drug reduced the risk of pathological or therapeutic progression of prostate cancer by 46%.

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However, the drug that crosses the blood-brain barrier has been associated with significant side effects, including decreased energy and libido, increased abdominal mass, and the possibility of worsening cardiovascular risks or complications, depression, bone demineralization, and hot flashes. Neil Shore, MD, ENACT Principal Investigator and Medical Director of the Karolinska Urological Research Center, Myrtle Beach, SC, said not all patients want to undergo AS, which can lead to cancer anxiety and has a high dropout rate. About 30% of men on AS stop treatment within 5 years due to cancer progression, and some urologists are urging patients with high volume low-risk prostate cancer to start treatment immediately.

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

“I think pharmaceutical companies would like to enter the ‘active surveillance market’. The problem is that there is no clear path to obtaining FDA approval under these conditions because clinical trial endpoints have not been validated,” Schweitzer said. “I think drugs can become part of the routine treatment for men with AS, but we need better ways to identify patients who need treatment.” These patients include those who, if left untreated, will require surgery or radiation therapy.

So far, drug makers say they are not interested in developing ARIs to treat low-risk cancers.

A spokesperson for Astellas, which partnered with Pfizer Oncology on the ENACT study, said the company has no plans to conduct additional early-stage prostate cancer studies and does not plan to release ENACT data to global regulators.

A spokesperson for Bayer Healthcare, a maker of darolutamide, which does not cross the blood-brain barrier, said the company is not sponsoring any in-house studies of its drug in low- or moderate-risk localized prostate cancer. But Bayer is supporting an independent study of intermediate-risk localized prostate cancer at the Dana-Farber Cancer Institute in Boston.

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Another mode of drug delivery that minimizes toxicity may encourage the use of ARIs.

Pamela Munster, MD, is a UC San Francisco oncologist and founder of Alessa Therapeutics. The company is developing Biolen, a silicon-based implantable seed that releases the drug directly into the prostate gland. She is conducting two pilot studies to determine whether drugs delivered locally can prevent the side effects of colds.

William Catalona, ​​MD, a pioneering urologist at Northwestern University’s Feinberg School of Medicine, said ARIs could hold a future for patients with low- and intermediate-risk conditions who would otherwise opt for AS or focal therapy.

“Of course, any form [ARI] It is expected to slow the progression of prostate cancer, and a benign disease with an average risk does progress more often and faster, so it deserves consideration,” said Catalona. “But what are the literal and actual costs?”

Most of his patients on enzalutamide, he says, “are not doing very well.” “Many suffer from severe fatigue, and some refuse to continue taking this medicine. Gynecomastia is also a problem for most men.”

While other drugs may delay progression with fewer side effects, “most patients under active surveillance are highly motivated to avoid the potential adverse side effects associated with prostate cancer treatment,” Catalona said.

He added that the final arbiter would be level 1 evidence from prospective randomized trials conducted by renowned investigators and published in prestigious journals. “Stay with us,” he said.

Munster is the founder and shareholder of Alessa Therapeutics. Schweizer received research funding from Janssen Pharmaceuticals. Shore received personal honoraria from Astellas and Pfizer during the study, as well as personal honoraria from Bayer, AstraZeneca, Janssen, Dendreon, Sanofi, Myovant and Merck. Booth, Catalona and Paller do not report any related financial relationships.

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

For more news, follow Medscape on Facebook, Twitter, Instagram and YouTube.

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