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ARAMIS final OS and nmCRPC safety outcomes

Prof. Karim Fizazi, Institut Gustave Roussy, France
ASCO 2020
Phase 3, ARAMIS
The final 3-year overall survival (OS) results for the ARAMIS trial (darolutamide vs placebo) in non-metastatic castration-resistant prostate cancer (nmCRPC) were positive. A head-to-head analysis of safety comparing darolutamide with apalutamide and enzalutamide data from other trials showed that for the general safety outcomes, there were no statistically significant differences after matching, although darolutamide showed an advantage for some specific adverse events.

ARAMIS was a randomised, double-blind, placebo-controlled, phase 3 trial in men with nmCRPC and a prostate-specific antigen doubling time of 10 months or less. Patients were randomly assigned to receive darolutamide (300 mg tablets twice daily) or placebo while continuing androgen-deprivation therapy. The primary endpoint of metastasis-free survival was already met [1]; however, there were questions as to whether the benefit of using androgen-inhibitors would translate to an OS benefit.

With a median follow-up of 29 months, Prof. Karim Fizazi (Institut Gustave Roussy, France) presented the final OS rates from ARAMIS, after 254 deaths had occurred (15.5% from the darolutamide arm, and 19.1% from the placebo arm), as being 83% and 77% on the darolutamide and placebo arms, respectively (n=1,509; HR 0.69; 95% CI 0.53-0.88; P=0.003) [2]. Importantly, darolutamide also met key secondary outcomes, including delaying time to pain progression, with a median 40.3 months versus 25.4 months with placebo (HR 0.65; 95% CI 0.53-0.79; P<0.001). Darolutamide also significantly delayed the time to first cytotoxic chemotherapy and time to first symptomatic skeletal event versus placebo. “These results provide compelling evidence for early darolutamide treatment in men with nonmetastatic CRPC,” concluded Prof. Fizazi.

In an interesting companion study, patient-level data from ARAMIS (darolutamide vs placebo, n=1,509) was compared with the SPARTAN (apalutamide vs placebo, n=1,207) and PROSPER (enzalutamide vs placebo, n=1,401) trials for safety outcomes. Dr Shan Jiang and colleagues applied a match-adjusted indirect comparison method to perform indirect treatment comparisons adjusting for cross-trial heterogeneity [3]. For the general safety outcomes, no statistically significant differences were observed between darolutamide and apalutamide or enzalutamide after matching. However, darolutamide showed a numeric advantage over both enzalutamide and apalutamide on adverse events leading to treatment discontinuation and adverse events leading to death, whereas apalutamide showed a numeric advantage over darolutamide on any serious adverse events. Among individual adverse events, darolutamide had a statistically significant lower risk of falls, fracture, and rash compared with apalutamide. Compared with enzalutamide, darolutamide had a lower risk of falls, dizziness, mental impairment, fatigue, and severe fatigue (see Figure).

In conclusion, this analysis suggests that, after adjusting for trial differences and multiple testing, darolutamide showed a generally favourable safety profile when compared to apalutamide and enzalutamide.
Figure. Differences in risk differences for darolutamide versus enzalutamide safety outcomes [3]

  1. Fizazi K, et al. N Engl J Med. 2019;380(13):1235-1246.
  2. Fizazi K, et al. ASCO Virtual Meeting, 29-31 May 2020, Abstract 5514.
  3. Jiang S, et al. ASCO Virtual Meeting, 29-31 May 2020, Abstract 5561.

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