Basel, Switzerland (UroToday.com) During this discussion, Dr. Gert Attard explained how to maximize therapy of steroids with abiraterone acetate. Abiraterone acetate is currently given for two indications:
- Newly diagnosed high-risk metastatic hormone-sensitive prostate cancer (mHSPC), with prednisone 5 mg daily.
- For metastatic castration-resistant prostate cancer (mCRPC) with prednisone 10 mg daily.
Abiraterone can cause mineralocorticoid access derived adverse effects, including hypokalemia, which has been reported in 11%, 2% and 3% in the abiraterone arm in the LATITUDE,1 COU-302,2 and COU-3013 trials, respectively.
The half-life of prednisone is less than 16 hours, while the half-life of dexamethasone is much longer (36-54 hours). Dexamethasone has a higher ratio of glucocorticoid to mineralocorticoid activity than prednisone. It also has greater activity as a single agent in mCRPC disease compared to prednisone.4 Approximately 25% of patients progressing on abiraterone with prednisone have a PSA decline after they are switched to dexamethasone.5,6
In a recently published study,7 various regimens of prednisone in combination with abiraterone were compared, including one arm with dexamethasone. The primary endpoint was no mineralocorticoid excess (grade ≥1 hypokalemia or grade ≥2 hypertension) through 24 weeks (6 cycles) from treatment. The study design is shown in figure 1. The results are shown in figure 2, including the rates of demonstrated hypokalemia. Of the 164 randomized men to prednisone 5 mg, twice daily, once daily, or 2.5 mg twice daily, or dexamethasone, 0.5 mg, once daily, 24/34 patients (70.6%, 95% CI, 53.8%-83.2%), 14/38 patients (36.8%, 95% CI, 23.4%-52.7%), 21/35 patients (60.0%, 95% CI, 43.6%-74.4%), and 26/37 patients (70.3%, 95% CI, 54.2%-82.5%), respectively, had no mineralocorticoid excess.
Interestingly, plasma adrenocorticotrophic hormone and urinary mineralocorticoid metabolites after 8 weeks of treatment were higher with prednisone, 2.5 mg, twice daily and 5 mg once daily than with 5 mg twice daily or dexamethasone, 0.5 mg, once daily. The level of urinary glucocorticoid metabolites appeared higher in patients who did not meet the primary endpoint, regardless of glucocorticoid regimen. It is important to note that the total lean body mass decreased in the prednisone groups and total body fat increased in the prednisone, 5 mg, twice daily and dexamethasone groups. In the dexamethasone group, there was an increase in serum insulin and insulin resistance, while total bone mineral density decreased.
The authors concluded that abiraterone acetate with prednisone, 5 mg, twice daily or dexamethasone, 0.5 mg, once daily met the prespecified threshold for the primary endpoint (95% CI excluded 50% mineralocorticoid excess). In contrast, abiraterone acetate with prednisone, 5 mg, once daily or 2.5 mg twice daily did not meet the threshold. Abiraterone acetate in combination with dexamethasone appeared to be especially active but may be associated with adverse metabolic consequences.
Figure 1 – Study design comparing various regimens of prednisone in combination with abiraterone:
Figure 2 – Final results of the study:
Dr. Attard concluded his talk stating that prednisone 5 mg BID and dexamethasone 0.5 mg once a day can minimize mineralocorticoid excess. However, this came at the cost of increased body fat for prednisone, and an increase in serum insulin and insulin resistance for dexamethasone. Prednisone 5 mg once daily minimizes the long-term physiological side effects but with a greater risk of mineralocorticoid excess. Dr. Attard emphasized that lower steroid doses require careful monitoring and ensuring that patients are medically optimized prior to beginning abiraterone.
Presented by: Gert Attard, MD, PhD, FRCP, John Black Charitable Foundation Endowed Chair in Urological Cancer Research, University College London Cancer Institute, London, UK
Written by: Hanan Goldberg, MD, Urology Department, SUNY Upstate Medical University, Syracuse, New-York, USA @GoldbergHanan at the 2019 Advanced Prostate Cancer Consensus Conference (APCCC) #APCCC19, Aug 29 – 31, 2019 in Basel, Switzerland
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- Gerhardt Attard, MD, PhD,corresponding author1 Axel S Merseburger, MD,2 Wiebke Arlt, MD, DSc,3 Cora N Sternberg, MD,4 Susan Feyerabend, MD,5 Alfredo Berruti, MD,6 Steven Joniau, MD, PhD,7 Lajos Géczi, MD,8 Florence Lefresne, MD,9 Marjolein Lahaye, MSc,9 Florence Nave Shelby, PhD,9 Geneviève Pissart, MSc,9 Sue Chua, MBBS,10 Robert J Jones, MBChB, PhD,11 and Bertrand Tombal, MD, PhD12 Assessment of the Safety of Glucocorticoid Regimens in Combination With Abiraterone Acetate for Metastatic Castration-Resistant Prostate Cancer A Randomized, Open-label Phase 2 Study. JAMA Oncol. 2019 Aug; 5(8): 1159–1167.