While androgen deprivation therapy has been the mainstay of treatment for men with metastatic prostate cancer, over the last decade multiple novel oral antiandrogens have been developed which are now commonly co-administered with ADT in advanced disease states. The most common of these, abiraterone acetate, is a pregnenolone analogue which acts on adrenal steroid precursors and consequently is administered with an oral corticosteroid to combat the adverse cardiac effects associated with mineralocorticoid excess. Despite this, previous randomized control trials have suggested increased cardiac risk with abiraterone plus ADT versus ADT alone. Here, we aim to summarize the available evidence regarding the cardiotoxicity of abiraterone via meta-analysis focusing on mechanistically related side-effects including hypokalemia and fluid retention, and further elucidate differences based on disease indication and use of steroids in the control population.
We performed and report a systematic review and meta-analysis in keeping with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. Cochrane, Embase, and Medline were searched for randomized controlled trials of abiraterone acetate published as of August 11, 2020. 2,739 abstracts were identified meeting the initial search criteria. We narrowed results to include phase II and III randomized control trials comparing abiraterone acetate to ADT alone in advanced prostate cancer disease states, ultimately identifying 6 relevant studies. Primary outcomes examined were all-grade and high-grade (grade ≥ 3) hypokalemia and fluid retention, and secondary outcomes included all-grade and high-grade hypertension and cardiac events. We performed random effects meta-analysis comparing intervention (abiraterone acetate + steroid) and control (placebo +/- steroid) with stratification according to treatment indication (CSPC, pre-chemo mCRPC, and post-chemo mCRPC) and to the use of steroid in the control arm.
3,178 patients with HSPC (including both mHSPC and advanced localized disease) or mCRPC were included. Treatment groups received abiraterone 1000mg daily with an oral corticosteroid and ADT, and controls received ADT and placebo +/- steroid. In the treatment groups versus the control, respectively, hypokalemia was observed in 16.7% versus 6.0% (OR 3.01, 95% CI 1.71-5.30, I2 = 87%), fluid retention was observed in 33.2% versus 24.7% (OR 1.51, 95% CI 1.22-1.87, I2 = 49.5%), hypertension was observed in 24.6% versus 14.7% (OR 1.85, 95% CI 1.39-2.45), and cardiac events were observed in 25.4% versus 15.9% (OR 1.77, 95% CI 121-2.58, I2 = 84%). Stratified analyses demonstrated significantly larger differences between abiraterone versus control when steroid was not administered for hypokalemia (p<0.00001) and hypertension (p=0.04). Similarly, significant differences were seen based on disease indication (greater effect of abiraterone in patients treated with mCSPC versus mCRPC) for hypokalemia (p<0.00001).
There is increased cardiotoxicity with the administration of abiraterone acetate with ADT versus ADT alone. Patients receiving abiraterone acetate earlier in the disease process (mCSPC as compared to pre- or post-chemo mCRPC) appear to have a greater magnitude of risk of hypokalemia but not other mechanistically-related cardiac events. These hypothesis-generating data require further validation, likely in the context of phase IV studies, but may be helpful in further assessing individualized risk.
ASSOCIATION BETWEEN DISEASE INDICATION AND STEROID USE AND MINERALOCORTICOID-RELATED TOXICITY OF ABIRATERONE ACETATE IN PATIENTS WITH ADVANCED PROSTATE CANCER: A META-ANALYSIS OF RANDOMIZED CONTROL TRIALS
Category
Prostate Cancer > Metastatic
Description
Presented By: Marybeth Hall
Authors: Marybeth Hall
Whitney J. Padgett
Aaron A. Laviana
Amy N. Luckenbaugh
Zachary Klaassen
Christopher J.D. Wallis