Enzalutamide is a novel AR signaling competitive inhibitor of androgen binding. It inhibits nuclear translocation of the AR, DNA binding, and coactivator recruitment. Enzalutamide binds the AR with a 5-8 fold greater affinity than bicalutamide. In the PROSPER trial, 1,401 patients were randomized 2:1 enzalutamide vs placebo, with a primary outcome of MFS 1. Secondary endpoints were time to PSA progression, time to first use of new therapy, and OS. Enzalutamide was associated with a 71% improvement of MFS (HR 0.29, 95%CI 0.24-0.35), as well as time to PSA progression (HR 0.07), and time to subsequent therapy (HR 0.21). At the interim analysis for OS, the HR was 0.80 (favoring enzalutamide) but was not statistically significant (p=0.15).
Apalutamide is a nonsteroidal anti-androgen AR inhibitor, which binds to the ligand-binding domain of the AR. AR inhibition is secondary to nuclear translocation and DNA binding, with 7-10 fold higher affinity than bicalutamide. The SPARTAN trial randomized 1,207 men 2:1 to receive apalutamide vs placebo 2. In the planned primary analysis at 378 events, median metastasis-free survival was 40.5 months in the apalutamide group compared with 16.2 months in the placebo group (HR for metastasis or death 0.28, 95%CI 0.23-0.35). Time to symptomatic progression was significantly longer with apalutamide than with placebo (HR 0.45, 95%CI 0.32-0.63). The rate of adverse events leading to discontinuation of the trial regimen was 10.6% in the apalutamide group and 7.0% in the placebo group.
As follows is a table comparing these two trials from @UroToday correspondent Dr. Thenappan Chandrasekar:
A previous network meta-analysis demonstrated that there was no significant difference in MFS (HR 1.04, 95% CI 0.78-1.37) for enzalutamide versus apalutamide 3. The ARAMIS trial demonstrated that darolutamide had a median MFS of 40.4 months vs 18.4 months with placebo (HR 0.41, 95%CI 0.34–0.50), representing a 59% reduction in metastases or death among patients receiving darolutamide 4. So, with now three medications in this disease space, which medication is best? Dr. Albers notes that in all three trials, overall survival was not reached with separation of the curves at ~18 months. In subsequent follow-up, it will be interesting to assess which trail has the strongest OS data, as this modality will likely decide the preferential treatment modality.
Dr. Albers made several concluding statements regarding darolutamide: (i) it has shown itself as an effective next-generation androgen receptor inhibitor; (ii) it has a better safety profile compared to enzalutamide and apalutamide; (iii) it will change practice if the MFS advantage translates to an OS advantage; (iv) it needs a strong selection (ie. PSA doubling time <6-10 months) in order to prevent overtreatment.
According to Dr. Albers, early AR-targeted treatment in M0 CRPC patients is not the new standard of care. In his opinion, new diagnostic tools such as 68Gallium-PSMA PET/CT will change the definition of the M0 state. Furthermore, the treatment costs of these drugs are considerable (30,000 € per year). Dr. Albers sees the future of M0 CRPC as every M0 CRPC patient with a PSA >2 having a 68Gallium-PSMA PET/CT and if there are multiple or visceral metastases they would then be started on next generation androgen receptor targeted therapy. If there are oligometastatic or single lymph node only metastases then they will get local treatment (salvage lymphadenectomy, radiation therapy, etc). If their 68Gallium-PSMA PET/CT shows no metastatic disease and their PSA doubling time is <6 months they would be started on next generation androgen receptor targeted therapy; if >6 months he advocates for watchful waiting and repeat imaging.
Presented by: Peter Albers, MD, University Hospital Dusseldorf, Dusseldorf, Germany
Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University - Medical College of Georgia Twitter: @zklaassen_md at the 34th European Association of Urology (EAU 2019) #EAU19 conference in Barcelona, Spain, March 15-19, 2019.
References:
1. Hussain M, Fizazi K, Saad F, et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2018 Jun 28;378(26):2465-2474.
2. Smith MR, Saad F, Chowdhury S, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med 2018;378(15):1408-1418.
3. Wallis CJD, Chandrasekar T, Goldberg H, et al. Advanced androgen blockage in nonmetastatic castration-resistant prostate cancer: An indirect comparison of apalutamide and enzalutamide. Eur Urol Oncol 2018 Apr 11 [Epub ahead of print].
4. Fizazi K, Shore N, Tammela TL, et al. Darolutamide in nonmetastatic castration-resistant prostate cancer. N Engl J Med. 2019 Feb 14 [Epub ahead of print].
Further Related Content:
Read: Darolutamide Receives FDA Approval for the Treatment of Non-metastatic Castration-resistant Prostate Cancer
Presentation by Professor Teuvo Tammela - Darolutamide Elicits a Strong PSA Response in Men with nmCRPC: Results from the ARAMIS Study