An ongoing phase II trial investigating abiraterone acetate (ZYTIGA) and enzalutamide (XTANDI) as treatment for men with chemotherapy-naïve metastatic castrate-resistant prostate cancer is aiming to characterize the effects of these targeted hormonal therapies on cognition and mood.
Chicago-An ongoing phase II trial investigating abiraterone acetate (ZYTIGA) and enzalutamide (XTANDI) as treatment for men with chemotherapy-naïve metastatic castrate-resistant prostate cancer (mCRPC) is aiming to characterize the effects of these targeted hormonal therapies on cognition and mood.
An initial analysis of data found that after 12 weeks of treatment, both agents were associated with adverse changes in cognitive function and depression severity, and there was a tendency for enzalutamide to have a greater impact on both. However, decrements to moderate or severe cognitive impairment or depression severity were rare with either treatment.
“Previous studies show that androgen ablation therapy affects cognition and mood, but there is very little known about the effects of these newer targeted therapies,” said first author Sunil Parimi, MD, genitourinary medical oncology fellow, British Columbia Cancer Agency, Vancouver, BC.
“The current study offers an opportunity to gain insight in this area, but it is still too early to reach any conclusions,” added Dr. Parimi, who worked on the study with Kim N. Chi, MD, and co-authors.
The primary objective of the phase II study is to evaluate sequencing and the efficacy of abiraterone and enzalutamide for men with chemotherapy-naïve mCRPC. The study has a crossover design. Men are randomized at baseline to treatment with abiraterone, 1000 mg daily with prednisone, 10 mg daily, or enzalutamide, 160 mg daily, and then they are switched to the alternate agent as second-line treatment upon PSA progression.
As part of the study protocol, information on depression is being collected with the Patient Health Questionnaire-9 (PHQ-9), and cognitive function is being assessed with the Montreal Cognitive Assessment (MoCA). Total scores for both instruments are categorized into four levels of severity: none, mild, moderate, or severe.
For the preliminary analysis of changes from baseline to week 12, data were available for 57 patients in each treatment arm. Baseline demographic and clinical characteristics were similar in the two groups as were median PHQ-9 and MoCA scores, which fell into the “none” category for the PHQ-9 and “mild” category for the MoCA. The proportions of patients within each of the four severity categories for both instruments were also similar comparing the two treatment arms. Overall, ≥98% of patients were categorized as having no or mild cognitive impairment at baseline and >90% of patients in both treatment arms had normal or mild severity ratings in depression.
From baseline to week 12, a significantly greater proportion of patients in the enzalutamide arm experienced worsening of their depression severity rating compared with the abiraterone arm (19% vs. 4%; p=.035). The proportion of patients experiencing worsening of cognitive impairment severity rating was also greater among enzalutamide-treated patients compared with the abiraterone group (13% vs. 2%), but the difference between groups only trended toward statistical significance (p=.06).
No patients in the abiraterone arm experienced a decrement to a moderate or severe category in their MoCA score, and such a change occurred for only 2.2% of men in in the enzalutamide arm. Worsening to a moderate or severe category in the depression rating occurred among 2% of men in the abiraterone arm and 6.1% of those in the enzalutamide arm.
An additional analysis evaluated worsening within each of the nine components in the PHQ-9, and its results showed the percentage of patients experiencing a decrement to a greater severity level was consistently higher in the enzalutamide treatment arm. While the difference between treatment arms was statistically significant only for psychomotor disabilities, there was a trend for a statistically significant difference in low energy (p=.017).
“We were particularly interested in whether low energy was driving the results since enzalutamide is known to cause fatigue. It appears, however, that a combination of factors may be contributing to the greater worsening of depression severity observed so far with enzalutamide,” Dr. Parimi told Urology Times.
Several of Dr. Parimi’s co-authors have an financial or other relationship with Janssen and/or Astellas Pharma and/or other pharmaceutical companies.
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