clinical topic updates
The Role of Novel Antiandrogens in Prostate Cancer Treatment
Targeting of the androgen axis has improved outcomes in patients with prostate cancer. Second-generation androgen receptor (AR) antagonists apalutamide, enzalutamide, and darolutamide extend metastasis-free survival in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC), and clinical trials are underway to compare and evaluate their use in other settings.
Professor of Medicine (Medical Oncology) and Urology
“With the recent US Food and Drug Administration approval of the second-generation AR antagonists apalutamide, enzalutamide, and darolutamide for nmCRPC, the treatment paradigm has changed for patients with nmCRPC who are at high risk for developing metastasis.”
In clinical trials of patients with nmCRPC, these novel antiandrogens extended metastases-free survival by approximately 2 years, which is a clinically meaningful improvement. Generally, darolutamide has the potential for fewer central nervous system side effects than apalutamide and enzalutamide because of its low penetration of the blood-brain barrier, as shown in preclinical studies. However, head-to-head trials are needed to determine the comparative toxicity profiles. Since this patient population frequently has preexisting comorbidities, I am mindful of the potential for drug-drug interactions and I understand that I may need to adjust the dose or consider an alternative second-generation AR antagonist for some individuals.
Advancements in imaging techniques may also transform the role of these agents in prostate cancer. While clinical trials evaluating the efficacy of novel AR antagonists in nmCRPC used conventional imaging, next-generation imaging provides a higher sensitivity in staging high-risk patients, which may identify patients with occult distant metastatic disease. The clinical implications of these findings are still unknown (ie, even if we change our treatment approach presumptively, based on advanced imaging, we do not yet know the impact that this will have on patient outcomes).
Prostate-specific antigen doubling time (PSADT) is a strong predictor of metastasis in this castration-resistant patient population and it serves to guide treatment. The recommendation for patients with a PSADT of greater than 10 months is observation rather than escalation of therapy. For a PSADT of 10 months or less, secondary hormone therapy (in addition to androgen deprivation therapy) would be an appropriate next step. Those with a PSADT of less than 6 months are at even greater risk.
With the recent US Food and Drug Administration approval of the second-generation AR antagonists apalutamide, enzalutamide, and darolutamide for nmCRPC, the treatment paradigm has changed for patients with nmCRPC who are at high risk for developing metastasis. Not long ago, there were no treatments for this stage. Enzalutamide is a second-generation AR antagonist that is specifically approved for metastatic CRPC. Clinical trials with apalutamide (TITAN trial) and darolutamide (ARASENS trial) are evaluating the use of these agents in the metastatic setting as well. There is also interest in investigating the use of novel antiandrogens in very high-risk patients earlier in the treatment paradigm.
Chi KN, Agarwal N, Bjartell A, et al; TITAN Investigators. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019;381(1):13-24. doi:10.1056/NEJMoa1903307
Fizazi K, Shore N, Tammela TL, et al; ARAMIS Investigators. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2019;380(13):1235-1246. doi:10.1056/NEJMoa1815671
Hussain M, Fizazi K, Saad F, et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2018;378(26):2465-2474. doi:10.1056/NEJMoa1800536
Liu Z, Zhang T, Ma Z, et al. Systemic management for nonmetastatic castration-resistant prostate cancer: a systematic review and network meta-analysis. Am J Clin Oncol. 2020;43(4):288-297. doi:10.1097/COC.0000000000000660
Mateo J, Fizazi K, Gillessen S, et al. Managing nonmetastatic castration-resistant prostate cancer. Eur Urol. 2019;75(2):285‐293. doi:10.1016/j.eururo.2018.07.035
Rice MA, Malhotra SV, Stoyanova T. Second-generation antiandrogens: from discovery to standard of care in castration resistant prostate cancer. Front Oncol. 2019;9:801. doi:10.3389/fonc.2019.00801
Smith MR, Saad F, Chowdhury S, et al; SPARTAN Investigators. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018;378(15):1408-1418. doi:10.1056/NEJMoa1715546
Smith MR, Saad F, Hussain M, et al. ARESENS: a phase 3 trial of darolutamide in combination with docetaxel for men with metastatic hormone-sensitive prostate cancer (mHSPC). J Clin Oncol. 2018;36(6 suppl):TPS383. doi:10.1200/JCO.2018.36.6_suppl.TPS383