Prostate Cancer Drug Linked to Lower Risk of Cognitive Decline

CHICAGO — Patients with advanced prostate cancer treated with enzalutamide (Xtandi) had a significantly greater decline in cognitive function compared with those who received darolutamide (Nubeqa), according to results from a phase II trial.

Median cognitive change in the maximally changed cognitive domain (MCCD) from baseline to 24 weeks was -15.8% for those receiving darolutamide versus -36.1% for those receiving enzalutamide (P=0.009), reported Alicia Morgans, MD, MPH, of the Dana-Farber Cancer Institute and Harvard Medical School in Boston.

The primary endpoint was assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB), which includes tests for executive function, visual memory, attention, and working memory.

“I think that this is informative of practice, but it doesn’t draw a black line here and say none of this drug and only that drug,” Morgans said during a press briefing in advance of the American Society of Clinical Oncology (ASCO) annual meeting. “I think that’s a very important take-home message. There’s also the take-home message that none of these patients — actually no one on trial, even at 48 weeks follow-up — has been diagnosed with dementia. These are cognitive changes on a cognitive test that is not diagnostic of any true clinical disorder.”

Darolutamide and enzalutamide are “two of the most commonly used androgen receptor pathway inhibitors in prostate cancer,” noted Morgans in explaining why she and her team compared the two drugs. “There are structural differences between these molecules that make it important to consider that they may have differential effects in the central nervous system and the brain.”

Darolutamide does not cross the blood-brain barrier to the extent that enzalutamide does, she pointed out. “And there are androgen receptors that are targeted by these drugs in the brain and central nervous system,” she added. “Targeting those central nervous system androgen receptors may cause differential effects in cognitive function.”

Commenting on the study, ASCO President Eric Small, MD, of the University of California San Francisco, said “most people” would agree that darolutamide’s lesser impact on cognitive function “may be explained by darolutamide’s limited ability to enter the brain.”

“Cognitive function decline is a limiting feature of our common treatments for advanced prostate cancer, and while it’s important to acknowledge the quantitative differences observed … it can be easy to lose the real-life context of these CANTAB domains,” he explained. “Just as critical is our experience about how devastating this cognitive loss can be. This is manifest in memory loss, executive function, falls, impaired functioning, lost jobs, getting lost in parking lots. It’s very variable amongst patients, but when it’s severe, it’s substantial.”

“Potentially, I think this offers an option for preserving cognitive health in men with advanced prostate cancer, so a very important study confirming what we’d observed clinically,” Small noted.

The prospective, open-label ARACOG trial included 111 men (median age 71, 83% white) in the U.S. with nonmetastatic castration-resistant, metastatic castration-resistant, or metastatic hormone-sensitive prostate cancer. Results were available for 95 patients — 48 who received darolutamide and 47 who received enzalutamide.

The CANTAB includes five remotely delivered cognitive tests that assess the following domains:

• Spatial working memory (SWM) — a measure of executive function and working memory
• Paired associate learning, first attempt memory (PALFAM) — visual memory and executive function
• One touch stockings — executive function and working memory
• Spatial span — working memory and visual memory
• Rapid visual information processing — attention and working memory

“There is overlap in these domains with these different tests, which is why it was important for us to use this broad, maximally changed cognitive domain on a test to ensure that we could capture that overlap,” Morgans explained.

In the study, the decline in MCCD in the SWM test at 24 weeks in the enzalutamide arm was significantly greater than the decline in the PALFAM test in the darolutamide arm.

Thus, the greatest cognitive change among those treated with darolutamide was in visual memory (i.e., getting lost in a familiar parking lot) and executive function, while those taking enzalutamide experienced a greater change in working memory (i.e., losing train of thought when telling a story), as well as executive function.

A key secondary endpoint was a comparison of crossover rates, with crossover occurring at 12 or 24 weeks if patients voiced a preference to cross from one treatment to another, and they experienced one of the following changes: ≥30% decline in any CANTAB module, ≥10-point decline in patient-reported Functional Assessment of Cancer Therapy-Cognition (FACT-Cog; perceived cognitive function), a fall or increased risk of falls, or a grade ≥2 neurologic toxicity event.

Even though a similar number of patients were eligible for crossover, there were 30 observed crossovers from enzalutamide to darolutamide and none from darolutamide to enzalutamide.

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