ASCO GU 2020: Implications for Adverse Effects and Development of Combination Therapies - The Effect of Deep AR Suppression with Enzalutamide or Apalutamide on Endogenous Glucocorticoids

San Francisco, California (UroToday.com) At Rapid Abstract Session A on Prostate Cancer at the 2020 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU), Dr. Nima Sharifi presented a series of results exploring the metabolic effects of enzalutamide and apalutamide and their potential implications for management of patients taking these medications.

Dr. Sharifi began his presentation by highlighting the fact that both enzalutamide and apalutamide are known to suppress the expression of the enzyme 11 β -hydroxysteroid dehydrogenase-2 (11B-HSD2). In normal physiology, this enzyme converts the glucocorticoid hormone cortisol to cortisone, which is metabolically inactive. This serves to “protect” mineralocorticoid receptors from cortisol, which is known to weakly stimulate them. This protective function is especially important in the kidney where mineralocorticoid stimulation is responsible for maintaining blood pressure and volume homeostasis.

Dr. Sharifi’s group, therefore, hypothesized that the inhibition of 11B-HSD2 by enzalutamide and apalutamide in noncancerous tissue would lead to systemic consequences. They demonstrated this in several separate experiments.

In the first experiment, they stained normal renal parenchymal tissue from patients who were not being treated for prostate cancer and underwent nephrectomy for renal carcinoma. This showed that the androgen receptor is consistently co-expressed with 11B-HSD2 in renal parenchymal cells of kidneys removed from men (92% of renal units) but not women (0%). This lends a plausible mechanism through which enzalutamide and apalutamide can affect 11B-HSD2 expression in these tissues.

Changes in glucocorticoid levels before and after initiation of enzalutamide/apalutamide were then assessed using blood samples from three separate clinical trials in which all participants received one of these two agents. These trials examined (i) neoadjuvant ADT + apalutamide for localized prostate cancer (25 patients), (ii) ADT + enzalutamide +/- PROSTVAC for nonmetastatic hormone-sensitive prostate cancer (38 patients), and (iii) enzalutamide +/- PROSTVAC for metastatic hormone-resistant prostate cancer (54 patients).

Cortisol levels in patients on trial increased relative to baseline in all three trials: 126.0 to 240.0 ng/ml (P < 0.001) in study 1; 114.0 to 142.0 ng/ml (P < 0.001) in study 2; and 116 to 153 ng/ml (P < 0.001) in study 3. To confirm that this rise was attributable to downregulated 11B-HSD2 expression, cortisol/cortisone ratios were measured in the same patients. A statistically significant rise supporting this mechanism was noted in the first two trials but the difference in the 3rd narrowly missed the cutoff of significance (p<0.001, p<0.001, and p=0.051 respectively).

Interestingly, only two patients were actually found to have new onset hypertension noted after initiation of therapy, though Dr. Sharifi did not go into detail regarding how these patients were identified and whether there might be others that were missed. On analysis of the urine markers THF (related to cortisol levels) and THE (related to cortisone levels), the patient with the greatest increase in SBP had a THF/THE ratio that was so high that it would have met the diagnostic criteria for inherited 11B-HSD2 deficiency were the under-expression of that enzyme in him not more likely attributable to his antiandrogen therapy. During the question and answer, Dr. Sharifi admitted that hypertension as a side effect of these medications is still relatively rare, and there is no way currently to predict which patients will actually develop hypertension in response to these medications, but these findings are nonetheless provocative.

Finally, Dr. Sharifi presented some data suggesting that the degree of 11B-HSD2 in response to these medications may be related to cancer outcomes. In the study of enzalutamide +/- PROSTVAC for metastatic hormone-resistant prostate cancer, patients in the enzalutamide-only arm seemed had a significantly lower progression-free survival when their cortisol/cortisone ratios were higher, suggesting that greater 11B-HSD2 inhibition may be indicative of more activity of enzalutamide overall. However in the enzalutamide + PROSTVAC arm the opposite was true, suggesting that the increased glucocorticoid expression may suppress the anti-tumor immune response in these patients.

These findings, while a long way off from affecting clinical practice in most cases, highlight that there is much more to be understood about the effects of novel antiandrogen agents on metabolism and possibly on the effectiveness of other concurrently-administered agents.

Presented By: Nima Sharifi, MD, Director of the Center for GU Malignancies Research, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio

Written by: Marshall Strother, MD, Society for Urologic Oncology Fellow, Division of Urologic Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania at the 2020 Genitourinary Cancers Symposium, ASCO GU #GU20, February 13-15, 2020, San Francisco, California 

References:

1. Alyamani, M., J. Li, M. Patel, S. Taylor, F. Nakamura, M. Berk, C. Przybycin et al. "Deep androgen receptor suppression in prostate cancer exploits sexually dimorphic renal expression for systemic glucocorticoid exposure." Annals of Oncology (2020).
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