ESMO 2021: Darolutamide Maintenance in mCRPC Previously Treated with Novel Hormonal Agents and Non-Progressive Disease After Subsequent Treatment with a Taxane: A Randomized Double-Blind Placebo-Controlled Phase II Trial (SAKK 08/16)

( The European Society of Medical Oncology (ESMO) 2021 annual meeting’s prostate cancer mini oral session included a presentation by Dr. Richard Cathomas discussing the phase II SAKK 08/16 trial assessing darolutamide maintenance in men with metastatic castration resistant prostate cancer (mCRPC) previously treated with novel hormonal agents and non-progressive disease after subsequent taxane therapy. The optimal treatment sequence for mCRPC remains unclear, with cross-resistance between novel hormonal agents, however with previous studies suggesting that chemotherapy may re-induce novel hormonal agent sensitivity.

Darolutamide is an androgen receptor antagonist with a distinct structure and potentially fewer side effects due to decreased blood-brain barrier penetration, previously showing a significant overall survival benefit in nmCRPC.1 Dr. Cathomas and colleagues hypothesized that maintenance treatment with darolutamide for patients with disease stabilization under chemotherapy after pretreatment with another novel hormonal therapy can delay disease progression.

SAKK 08/16 is a randomized placebo-controlled double-blind phase 2 study. Patients with mCRPC and prior novel hormonal agent therapy and non-progressive disease on taxane (docetaxel >=300mg/m2 or cabazitaxel >=80mg/m2) were eligible. Patients received darolutamide 600mg bd or placebo bd starting 2-8 weeks after end of taxane. The SAKK 08/16 study design is as follows: 

SAKK 08/16-0.jpg 

The primary endpoint for this study was radiographic progression-free survival at 12 weeks (rPFS12). Secondary endpoints included: rPFS, event-free survival (EFS), overall survival (OS), PSA 50% response (PSA50 RR), adverse events. A total of 88 patients were needed to show superiority of darolutamide for rPFS12 (type I error 15%, power 80%).

There were 92 patients accrued between March 2017 and November 2020, with 90 patients included in the full analysis set. The median follow-up was 18 months, the median age was 72 years (range: 55-87), and the prior taxane therapy used was docetaxel in 93% of patients and cabazitaxel in 7% of patients. The prior novel hormonal agent was abiraterone in 60%, enzalutamide in 31%, and both agents in 9% of patients. The primary endpoint of rPFS12 was significantly improved with darolutamide 64.7% versus placebo 52.2% (p=0.127, below significance level of 0.15). The key secondary endpoint of median rPFS on darolutamide was 5.5 months versus 4.5 months on placebo (HR 0.54; 95% CI 0.32-0.91; p=0.017):

SAKK 08/16-1.jpg 

The median EFS was 5.4 months versus 2.9 months (HR 0.46, 95% CI 0.29-0.73; p=0.001), and median OS on darolutamide was 24 months versus 21.3 months on placebo (HR 0.62, 95% CI 0.3-1.26; p= 0.181):

SAKK 08/16-2.jpg 

PSA50 RR was 22% on darolutamide vs 4% on placebo (p=0.014). Treatment related adverse events were mild and similar in both arms (darolutamide vs placebo): grade 1: 26% vs 22%; grade 2: 13% vs 15%; grade 3: 2% vs 2%. Fatigue grade 1/2 was less common in darolutamide arm (11% vs 20%).

Dr. Cathomas concluded his presentation of the SAKK 08/16 with the following take-home messages:

  • This proof of concept study met its primary endpoint and shows that switch maintenance with darolutamide after prior taxane and at least one novel hormonal agents results in a statistically significant but clinically modest prolongation of rPFS and EFS with good tolerability
  • Median OS with darolutamide maintenance is promising and numerically superior to the control arm
  • Prior response to a novel hormone agent may predict benefit from maintenance treatment after novel hormone agents and taxane therapy

Presented by: Richard Cathomas, MD, Oncology/Hematology, Kantonsspital Graubünden, Chur, Switzerland 

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2021 European Society for Medical Oncology (ESMO) Annual Congress 2021, Thursday, Sep 16, 2021 – Tuesday, Sep 21, 2021.


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