Next-Generation AR Inhibitors Retain their Role in Nonmetastatic CRPC

Evan Y. Yu, MD

Despite the availability of next-generation PET imaging modalities that can detect metastasis earlier, apalutamide (Erleada), enzalutamide (Xtandi), and darolutamide (Nubeqa) remain the standard of care for patients with nonmetastatic castration-resistant prostate cancer (M0CRPC) who have a prostate-specific antigen (PSA) doubling time of less than 10 months, said Evan Y. Yu, MD.

“We now have very sensitive imaging modalities, but the impact of finding and treating patients differently based on those for M0CRPC is really quite unknown at this point in time,” said Yu, a professor in the Department of Medical Oncology at the University of Washington School of Medicine, a member in the Clinical Research Division at Fred Hutchinson Cancer Research Center, and clinical trials core director of Genitourinary Medical Oncology at Seattle Cancer Care Alliance, in a presentation during a 2020 Institutional Perspectives in Cancer webinar on prostate cancer.

Currently, the patients with M0CRPC are eligible for 1 of 3 next-generation androgen receptor (AR) inhibitors, apalutamide being the first studied in a randomized phase 3 trial. In the SPARTAN trial, patients were randomized 2:1 to 240 mg of daily apalutamide plus androgen deprivation therapy (ADT) or placebo plus ADT. Similarly, in the phase 3 PROSPER trial, patients were randomized 2:1 to 160 mg of daily enzalutamide plus ADT or placebo plus ADT. Additionally, the phase 3 ARAMIS trial randomized patients 2:1 to 1200 mg of darolutamide twice daily plus ADT or placebo plus ADT.

Each trial required that patients have nonmetastatic CRPC, a baseline PSA level of at least 2 ng/mL, and a PSA doubling time of 10 months or less. Metastasis-free survival (MFS) and overall survival (OS) served as the primary and secondary end points of each study, respectively.

“You can’t really do cross-trial comparisons, but you can see that all of them are very statistically significant [and have a] very significant MFS benefit,” said Yu (Table).^1-3

Table. Comparison of the primary end point of randomized phase 3 trials in M0CRPC

Table. Comparison of the primary end point of randomized phase 3 trials in M0CRPC

The OS for each of the 3 trials was also positive, said Yu. In SPARTAN, apalutamide led to a 22% reduction in the risk of death versus placebo (HR, 0.78; 95% CI, 0.64-0.96; P = .0161).⁴ The median OS was 73.9 months with apalutamide versus 59.9 months with placebo. In PROSPER, enzalutamide led to a 27% reduction in the risk of death versus placebo (HR, 0.73; 95% CI, 0.61-0.89; P = .001).⁵ The median OS was 67.0 months and 56.3 months, respectively.

In ARAMIS, darolutamide led to a 31% reduction in the risk of death (HR, 0.69; 95% CI, 0.53-0.88; P = .003).⁶ Because of the short follow-up, the median OS has not been reached, said Yu.

In terms of safety, Yu called attention to the increased likelihood of fatigue (37.0% vs 16.0%), hypertension (18.0% vs 6.0%), rash (4.0% vs 3.0%), falls (18.0% vs 5.0%), fractures (18.0% vs 6.0%), and mental impairment (8.0% vs 2.0%) with enzalutamide versus placebo in PROSPER and the increased likelihood of rash (26.0% vs 6.3%), falls (22.0% vs 9.5%), and fractures (18.0% vs 7.5%) with apalutamide versus placebo in SPARTAN.

Despite the increased incidence of these adverse effects, health-related quality of life was maintained with each agent versus placebo, added Yu.

“I am not obtaining [next-generation PET imaging] for M0CRPC for practical reasons because the trials didn’t do it that way, and we have agents that we can use. If patients do have next-generation PET imaging results that are positive, but the conventional CT and bone scan results are negative, I still feel comfortable treating them as if they have M0CRPC because they fit the eligibility criteria for these studies,” concluded Yu.

References

1. 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. doi:10.1056/NEJMoa1715546

2. 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

3. Fizazi K, Shore N, Tammela TL, et al. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2019;380(13):1235-1246. doi:10.1056/NEJMoa1815671

4. Small EJ, Saad F, Chowdhury S, et al. Final survival results from SPARTAN, a phase III study of apalutamide versus placebo in patients with nonmetastatic castration-resistant prostate cancer. J Clin Oncol. 2020;38(suppl 15):5516. doi:10.1200/JCO.2020.38.15_suppl.5516

5. Sternberg CN, Fizazi K, Saad F, et al. Enzalutamide and survival in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2020;382(23):2197-2206. doi:10.1056/NEJMoa2003892

6. Fizazi K, Shore N, Tammela TL, et al. Nonmetastatic, castration-resistant prostate cancer and survival with darolutamide. N Engl J Med. 2020;383(11):1040-1049. doi:10.1056/NEJMoa2001342