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Another Link Between Prostate Cancer Hormone Tx and Impaired Cognition

— Strongest association with enzalutamide, but survival benefit outweighs effect, specialists say

MedpageToday
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Hormonal therapy for advanced prostate cancer, particularly enzalutamide (Xtandi), had a significant association with cognitive impairment, an analysis of a large drug-safety database showed.

Traditional hormonal therapy increased the odds of cognitive impairment by 47% versus men who did not receive the therapy. The odds more than doubled among men who received novel androgen receptor signaling inhibitors (ARSIs), according to Alicia K. Morgans, MD, of Dana-Farber Cancer Institute in Boston, and colleagues.

An analysis by type of ARSI showed about a threefold increase in the odds of cognitive impairment for men treated with enzalutamide or apalutamide (Erleada), achieving statistical significance only with the former. In contrast, abiraterone (Zytiga) was associated with a decreased risk of cognitive impairment, they stated in .

"This study demonstrates elevated odds of neurocognitive impairment with hormone therapy in a real-world dataset," Morgans and colleagues said. "Due to limitations inherent to disproportionality analysis ... and incomplete data prohibiting the ability to control for factors such as age or use of secondary drugs (e.g., concurrent use of novel ARSIs with ADT [androgen deprivation therapy]), results are exploratory in nature."

"The amalgamation of these and other conflicting data my contribute to clinical decision making for men with prostate cancer eligible for treatment with these therapies, especially those with significant neurologic comorbidities," they said.

The results are consistent with those of a recent analysis of patient-reported outcomes from the pivotal of enzalutamide, showing a significant decline in cognitive function in association with significant improvement in survival in metastatic hormone-sensitive prostate cancer.

"Enzalutamide was associated with improved deterioration-free survival for OHQL [overall health and quality of life (QoL)], physical function, and cognitive function because delays in disease progression outweighed early deteriorations in these aspects of HRQL [health-related quality of life]," concluded Martin R. Stockler, MD, of the University of Sydney, and colleagues, in the .

In an exclusive ֱ video commentary, urologist Eric Klein, MD, of the Cleveland Clinic, agreed that the survival benefits demonstrated by enzalutamide outweighed the QoL detriments, including cognitive impairment.

"These clinically significant declines [in OHQL] occurred in just a minority of the patients," said Klein. "And, in fact, most patients did not report much in the way of severe symptoms. The effects were mostly evident in the early treatment course and remain stable over time, meaning that they did not get worse with longer duration of treatment, which is important because these agents tend to be used over a long period of time."

"The benefits of enzalutamide in delaying disease progression with respect to survival, disease-related symptoms, and delaying the need for additional therapy seem to outweigh modest early declines in some QoL domains," he added. "As a result of all of this, it's clear enzalutamide is well tolerated and should be the standard of care in conjunction with androgen deprivation in men with metastatic hormone-sensitive prostate cancer."

In their background material, Morgans and colleagues cited conflicting evidence about the association between hormonal therapy for prostate cancer and neurocognitive impairment. Recent of ADT in prostate cancer also showed that the data relative to cognitive function are .

Limited data have come from studies of the neurocognitive effects of different types of hormonal therapies, Morgans and colleagues said. One recent meta-analysis showed associations between novel nonsteroidal antiandrogens and fatigue, falls, headache, and dizziness, and the associations appeared stronger for enzalutamide than for darolutamide (Nubeqa) and apalutamide.

To continue the investigation into hormonal therapy and neurocognitive function, Morgans and colleagues analyzed data from , the World Health Organization global database of individual safety reports. Encompassing case reports from January 1968 through December 2019, the analysis comprised 170,760 adverse drug reports (ADRs) associated with hormone therapy and 87,541 reports neurocognitive ADRs. Comparison of the two types of ADRs showed 1,762 overlapping reports, which formed the basis for the primary analysis.

For purposes of the study, investigators defined traditional hormonal therapy as ADT (gonadotropin-releasing-hormone agonists or antagonists) or first-generation androgen receptor (AR) antagonists. Novel ARSIs included ARSIs with or without ADT. Statistical significance was defined as Empirical Bayes Estimator (EBE) values ≥1.0.

The analysis yielded a relative odds ratio (ROR) for neurocognitive impairment of 1.47 for traditional hormone therapy (95% CI 1.34-1.62, EBE=1.35), increasing to 2.40 for novel ARSIs (95% CI 2.28-2.54, EBE=2.26). Further analysis showed a significant association between enzalutamide and neurocognitive impairment (ROR 2.89, 95% CI 2.73-3.05, EBE=2.70) and a numerical association for apalutamide (ROR 3.31, 95% CI 1.57-7.00, EBE=0.98). Abiraterone was associated with a numerically decreased odds for neurocognitive impairment (ROR 0.68, 95% CI 0.55-0.84, EBE=0.57).

The authors acknowledged that the study did not establish causality between hormonal therapy and cognitive impairment, but they said the real-world nature of the data likely make the study "generalizable to the heterogeneous population of men using these agents."

"While further study is needed in this space to establish causality, pharmacovigilance findings may be considered exploratory in nature," they added. "It should also be noted that because reports can be submitted without being complete, there are a large amount of missing demographic data, making it difficult to identify or control for underlying risk factors for developing adverse events."

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    Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined ֱ in 2007.

Disclosures

Morgans disclosed relationships with Astellas, AstraZeneca, Advanced Accelerator Applications, Bayer, Clovis, Dendreon, Exelixis, Myovant, Novartis, Pfizer, Sanofi, Blue Earth, Lantheus, and Myriad.

The ENZAMET study was supported by Astellas.

Stockler disclosed relationships with Astellas, Celgene, Bayer, Bionomics, Medivation, Sanofi, Pfizer, AstraZeneca, Bristol Myers Squibb, Roche, Amgen, Merck Sharp & Dohme, Tilray, and BeiGene.

Primary Source

Prostate Cancer and Prostatic Diseases

Briggs LG, et al "Neurocognitive impairment associated with traditional and novel androgen receptor signaling inhibitors ± androgen deprivation therapy: A pharmacovigilance study" Prostate Cancer Prostatic Dis 2022; DOI: 10.1038/s41391-022-00541-6.

Secondary Source

Journal of Clinical Oncology

Stockler MR, et al "Health-related quality of life in metastatic, hormone-sensitive prostate cancer: ENZAMET (ANZUP 1304), an international, randomized phase III trial led by ANZUP" J Clin Oncol 2022; DOI: 10.1200/JCO.21.0094.