ADT & HORMONAL THERAPY

HORMONAL THERAPY 
​Enzalutamide, apalutamide and based on the Aramis trial, darolutamide are all approved by the FDA for nmCRPC.  (6) 

​Abiraterone, apalutamide, enzalutamide have all been associated with increased risk of non-pathologic fractures. (COU-AA-301 trial, SPARTAN).  

ADT
Testosterone normally declines 3.2 to 3.5ng/dl per year in health middle aged men​. (13,14)  Intermediate risk get 4-6 months of ADT and high risk gets 18-36mo.  Longer duration increases risk of DM, BMD loss, metabolic syndrome, possibly cardiac disease, especially if underlying cardiac conditions and affects QOL. (1)  A RCT of high risk PCa patients showed no difference in survival between 18 and 36mo of ADT with 18mo having better QOL. (3)

One study analyzing 6 phase 3 trials found GNRH agonists may have higher risk of CV events or death during 1st year of ADT.  GNRH antagonists had a 40$ reduced CV event or death.  Among patietns with preexisting CV disease, GNRH antagonist (degarelix) had a HR of 0.44 for CV or death.   (20)  In the frist prospective trial to look at CV outcomes, GnRH antagonists had less cardiovascular and cerebrocvascular events (3%) vs. 20% in GnRH agonists. (21)

The GNRH2 allele may be suitable candidates for intense suppression for serum testosterone during ADT and serum testosterone may be inadequately suppressed in patients with this allele. (2)All patients on ADT should be started on Vitamin D and calcium and baseline DEXA scan and fracture risk assessment.

SIDE EFFECTS OF ADT
​BONE HEALTH - Bone mineral density falls by 2-6% in lumbar spine and 2-4% of hip in first 1-2 years of ADT, as shown on DEXA scans in one study. (8) A large study of 80,000 SEER prostate cancer patients found ADT associated with a 34% increase in risk of fracture in patients with nmPCa and a 51% increase in mPCa. (12) A large retrospective study found a hazard ratio of 1.4 for all fractures in patients with ADT compared to without. (4) There may be an increase in QT associated with ADT. (5)   Transdermal estradiol has been used in past to treat hot flashes. (7-11)

CARDIOVASCULAR - GnRH antagonists have been found to have fewer cardiovascular events than agonists. (16) 

COGNITIVE FUNCTION - A systematic review and meta-analysis in 2021 found that in their study there was a HR of 1.21 for dementia risk associated with ADT use with this increaing to 1.36 if used more than 12mo. (22) One RCT of 308 patients with PCa on ADT found at 6 months of LHRH agonist therapy cognitive performance was not sustantially affected. (15) 

INTERMITTENT VS CONTINUOUS
Some RCT have shown improved quality of life when ADT is intermittent.  (17,18) One retrospective study found decreased rates of CHF and bone fractures. (19)
  1. Gansler, Ted, et al. "most Gleason 8 Biopsies are Downgraded at Prostatectomy—does 4+ 4= 7?." The Journal of urology 199.3 (2018): 706-712.
  2. Shiota, Masaki, et al. "The Association of Polymorphisms in the Gene Encoding Gonadotropin-Releasing Hormone with Serum Testosterone Level during Androgen Deprivation Therapy and Prognosis of Metastatic Prostate Cancer." The Journal of urology 199.3 (2018): 734-740.
  3. Nabid, Abdenour, et al. "Duration of androgen deprivation therapy in high risk prostate cancer: Final results of a randomized phase III trial." (2017): 5008-5008.
  4. Wallander, M., et al. "Patients with prostate cancer and androgen deprivation therapy have increased risk of fractures—a study from the fractures and fall injuries in the elderly cohort (FRAILCO)." Osteoporosis International (2018): 1-11.
  5. Gagliano-Jucá, Thiago, et al. "Androgen Deprivation Therapy Is Associated With Prolongation of QTc Interval in Men With Prostate Cancer." Journal of the Endocrine Society 2.5 (2018): 485-496.
  6. Fizazi, K., Shore, N., Tammela, T. L., Ulys, A., Vjaters, E., Polyakov, S., … Kuss, I. (2019). Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer. The New England Journal of Medicine, 380(13), 1235–1246.​
  7. Russell, Nicholas, et al. “Short-Term Effects of Transdermal Estradiol in Men Undergoing Androgen Deprivation Therapy for Prostate Cancer: A Randomized Placebo-Controlled Trial.” European Journal of Endocrinology, vol. 178, no. 5, 2018, pp. 565–576.
  8. Choo, Richard, et al. “Randomized, Double-Blinded, Placebo-Controlled, Trial of Risedronate for the Prevention of Bone Mineral Density Loss in Nonmetastatic Prostate Cancer Patients Receiving Radiation Therapy Plus Androgen Deprivation Therapy.” International Journal of Radiation Oncology Biology Physics, vol. 85, no. 5, 2013, pp. 1239–1245.
  9. Alibhai, S. M. H., et al. “Changes in Bone Mineral Density in Men Starting Androgen Deprivation Therapy and the Protective Role of Vitamin D.” Osteoporosis International, vol. 24, no. 10, 2013, pp. 2571–2579.
  10. Brown, Sue A., and Theresa A. Guise. “Cancer Treatment-Related Bone Disease.” Critical Reviews in Eukaryotic Gene Expression, vol. 19, no. 1, 2009, pp. 47–60.
  11. Greenspan, Susan L., et al. “Bone Loss after Initiation of Androgen Deprivation Therapy in Patients with Prostate Cancer.” The Journal of Clinical Endocrinology and Metabolism, vol. 90, no. 12, 2005, pp. 6410–6417.
  12. Beebe-Dimmer, Jennifer L., et al. “Timing of Androgen Deprivation Therapy Use and Fracture Risk among Elderly Men with Prostate Cancer in the United States.” Pharmacoepidemiology and Drug Safety, vol. 21, no. 1, 2012, pp. 70–78.
  13. Zmuda, J. M., Cauley, J. A., Kriska, A., Glynn, N. W., Gutai, J. P., & Kuller, L. H. (1997). LONGITUDINAL RELATION BETWEEN ENDOGENOUS TESTOSTERONE AND CARDIOVASCULAR DISEASE RISK FACTORS IN MIDDLE-AGED MEN. A 13-YEAR FOLLOW UP OF FORMER MULTIPLE RISK FACTOR INTERVENTION TRIAL PARTICIPANTS. American Journal of Epidemiology, 146(8), 609–617.
  14. Harman, S. M., Metter, E. J., Tobin, J. D., Pearson, J., & Blackman, M. R. (2001). Longitudinal Effects of Aging on Serum Total and Free Testosterone Levels in Healthy Men. The Journal of Clinical Endocrinology and Metabolism, 86(2), 724–731.
  15. Morote, J., Tabernero, Á. J., Ossorio, J. L. Á., Ciria, J. P., Domínguez-Escrig, J. L., Vázquez, F., … Romero, J. (2017). Cognitive Function in Patients With Prostate Cancer Receiving Luteinizing Hormone-Releasing Hormone Analogues: A Prospective, Observational, Multicenter Study. International Journal of Radiation Oncology Biology Physics, 98(3), 590–594.
  16. Albertsen, Peter C., et al. “Cardiovascular Morbidity Associated with Gonadotropin Releasing Hormone Agonists and an Antagonist.” European Urology, vol. 65, no. 3, 2014, pp. 565–573.
  17. Crook, J. M., et al. “Intermittent Androgen Suppression for Rising PSA Level after Radiotherapy.” The New England Journal of Medicine, vol. 367, no. 10, 2012, pp. 895–903.
  18. Miller, K., et al. “Randomised Prospective Study of Intermittent versus Continuous Androgen Suppression in Advanced Prostate Cancer.” ASCO Meeting Abstracts, vol. 25, 2007, p. 5015.
  19. Tsai, Huei-Ting, et al. “Risks of Serious Toxicities from Intermittent versus Continuous Androgen Deprivation Therapy for Advanced Prostate Cancer: A Population Based Study.” The Journal of Urology, vol. 197, no. 5, 2017, pp. 1251–1257.
  20. Albertsen, Peter C., et al. "Cardiovascular morbidity associated with gonadotropin releasing hormone agonists and an antagonist." European urology 65.3 (2014): 565-573.
  21. Margel, David, et al. "Cardiovascular morbidity in a randomized trial comparing GnRH agonist and GnRH antagonist among patients with advanced prostate cancer and preexisting cardiovascular disease." The Journal of urology 202.6 (2019): 1199-1208.
  22. ​Sari Motlagh, Reza, et al. "The Risk of New Onset Dementia and/or Alzheimer Disease among Patients with Prostate Cancer Treated with Androgen Deprivation Therapy: A Systematic Review and Meta-Analysis." The Journal of urology 205.1 (2021): 60-67.
Proudly powered by Weebly