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SAN FRANCISCO -- Two widely used androgen receptor signaling inhibitors (ARSIs) had a similar overall effect on cognitive function in men with metastatic castration-resistant prostate cancer (mCRPC) but differed significantly for specific components of cognition and mood, a prospective observational study showed.

Patients had more fatigue, depression, and perceived deterioration in cognitive function when treated with enzalutamide (Xtandi) versus abiraterone (Zytiga). Reaction time also slowed significantly during the first 6 months of treatment with enzalutamide.

The findings should help inform decision-making for patients who are candidates for either of the two drugs, reported Amit Bahl, MBBS, MD, of University Hospitals Bristol in England, at the Genitourinary Cancers Symposium.

"This is an important consideration for treatment optimization and ensuring supportive strategies for the patients when using these drugs, keeping in perspective the cognitive function assessment at baseline and subsequently on treatment," said Bahl.

During a discussion that followed the presentation, an unidentified member of the audience asked Bahl how he would share information with patients about the quality-of-life (QoL) differences between abiraterone and enzalutamide.

"I think that's the crux of the whole study because it should [be implemented] in our clinical practice," said Bahl. "I've always wondered when we talk about pre-assessment of our patients for any systemic therapy, whichever guideline you look at, cognitive function assessment actually is just a factor put in, but there are no points given to that calculation. I think we need to get cognitive function baseline assessment as a factor before we start to engage with our patients regarding this conversation of how we assess this data and how we implement it."

"More importantly, it has an impact, which we've not shown yet but expect in our 1-year time point, a quality-of-life impact," Bahl continued. "That is an assessment when we are talking with patients and discussing the aspects, it's not just about living longer, it's about living better, as well."

Steven Vogl, MD, of New York City, asked Bahl whether switching drugs might help avoid the adverse cognitive effects, noting that darolutamide (Nubeqa) does not cross the blood-brain barrier.

Pointing out that darolutamide is not approved for mCRPC, Bahl said, "I hear that a lot about darolutamide, not crossing the blood-brain barrier, but I think we need to be cognizant that there are changes in cognitive function not just because of blood-brain barrier transmission but that other factors are at play, as well."

The potential adverse cognitive effects of ARSIs and androgen deprivation therapy (ADT) have attracted considerable research attention in recent years. Several recent reviews and meta-analyses have shown no consistent pattern of adverse effects.

A recent analysis of a drug-safety database, focusing specifically on ARSIs, showed that treatment with enzalutamide or apalutamide (Erleada) significantly increased the odds of cognitive impairment, whereas abiraterone was associated with a reduced risk. The phase III randomized trial that helped establish enzalutamide as frontline therapy for mCRPC worsening fatigue, physical function, and cognitive function in patients treated with the ARSI. The authors concluded that the drug's effect on disease progression clearly outweighed the adverse effects.

Seeking more information to help optimize treatment selection and promote planning for supportive care, investigators in the multicenter ACE study enrolled patients with newly diagnosed mCRPC. Investigators used the instrument to assess cognitive function. Other assessments included the FACT-Cog (cognitive function), FACT-F (fatigue), and PHQ-9 (depression). Patients had a baseline assessment and follow-up assessments after 3-4 months, 6 months, and 12 months of treatment. Bahl reported findings from the first two assessment time points.

Treatment was not randomized, as the choice of ARSI was left to the individual investigators. The study population comprised 253 patients at baseline, decreasing to 184 at 3-4 months and 131 at 6 months.

The two treatment groups did not differ in the mean composite cognitive outcome at 3-4 months (P=0.553) or 6 months (P=0.198). Investigators also found no significant differences in spatial working memory, rapid information processing, or spacial information processing.

The enzalutamide group had significant deterioration in reaction time task relative to abiraterone at 3-4 months (P=0.009) and 6 months (P=0.037). Across both time points, mean fatigue score deteriorated significantly in the enzalutamide arm but not with abiraterone. Between-group values also differed significantly at 3-4 and 6 months (P<0.001). PHQ-9 depression scores increased with enzalutamide and differed significantly from abiraterone at 3-4 (P=0.001) and 6 months (P=0.036).

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