Darolutamide maintenance shows promise in pretreated mCRPC

Findings from the phase 2 SAKK 08/16 trial shared during the 2021 ESMO Congress showed that maintenance therapy with darolutamide (Nubeqa) led to a statistically significant but clinically modest progression-free survival (rPFS) and event-free survival (EFS) benefit in pretreated patients with metastatic castration-resistant prostate cancer (mCRPC).

Patients had received at least 1 novel hormonal agent and had non-progressive disease after subsequent treatment with taxane-based therapy. The study met its primary end point and 1 secondary end point. The treatment was also found to be tolerable in patients.

The introduction of NHAs has led to an evolution in the prostate cancer treatment paradigm. Based on the signal of efficacy with NHAs, and the survival observed with darolutamide in 2 prior studies investigators hypothesized that progression of disease might be delayed with an immediate switch to darolutamide in patients with disease stabilization under chemotherapy following pretreatment with another NHA.

“We have heard a lot about the changing treatment landscape in mCRPC in the past years and so many different agents have been introduced, and however the optimal treatment sequence remains unclear. darolutamide is an androgen receptor antagonist who has a distinct structure with potentially fewer side effects due to decreased blood-brain barrier penetration,” said Richard Cathomas of Kantonsspital Graubünden, during the ESMO presentation.

In the randomized placebo-controlled double-blind SAKK 08/16 trial, 92 patients were included and randomized 1:1 at 26 centers across Switzerland, Italy, Spain, and France to receive darolutamide 600 mg twice daily or matching placebo starting 2 to 8 weeks after the end of taxane-based therapy.

Patients with stratified by country, WHO performance status, prior therapy, site of metastases, and planned start of study treatment following taxane-based therapy.

At baseline, the darolutamide had a median age of 71 years (range, 56-81). The WHO performance score in the group was 0 in 100% of patients. Sites of metastasis included bone (87%), lymph node (51%), liver (2%), and lung (2%). The majority of the darolutamide arm (53%) had a Gleason score between 8 and 10. Finally, the time from the end of taxane to the start of darolutamide was 35 days or more in 51% of patients.

In the placebo arm, the median age was 72 years (range, 55-87). Ninety-eight percent of patients in the control arm had a WHO performance score of 0. Metastatic sites were the same as the darolutamide arm with 89% of patients having bone metastases, 51% having lymph node metastases, and 2% and 4% respectively having liver or lung metastases. Also, mirroring the darolutamide arm, 53% of patients in the placebo arm had a Gleason score between 8 and 10. Following taxane-based therapy, 53% of patients in the control arm started placebo after 35 days or more.

Looking at prior NHA therapy in the darolutamide arm compared with the placebo arm, 60% of patients in each group received prior abiraterone (Zytiga) and 31% received enzalutamide (Xtandi). Also, 9% of patients in each arm received both. Largely, response to previous treatment included partial responses (PRs) including in 24% of the experimental arm versus 33% of the control arm. Further, 36% of the darolutamide arm versus 38% of the control arm achieved stable disease (SD) on their prior therapy.

Prior taxane therapy was also acknowledged at baseline and the information showed that 96% of the darolutamide arm received docetaxel compared with 87% of the placebo arm, and 4% received cabazitaxel versus 13%, respectively. Although best responses to taxane therapy were complete responses (CRs), most patients had a PR, including 29% of the darolutamide arm and 42% of the control arm. SD was achieved with taxane therapy in 69% compared with53%, respectively.

In addition to assessing rPFS at 12 weeks, the study’s secondary end points included rPFS, EFS, overall survival (OS), prostate-specific antigen response of 50% (PSA50), and safety determine by adverse events (AEs).

The study was 80% powered to detect improvement in rPFS at 12 weeks with darolutamide. At a median follow up of 18 months, the 12-months rPFS with darolutamide was 64.7% (95% CI, 47.6%-77.5%) compared with 52.2% (95% 36.1%-66.1%) in the placebo arm (P =.127). The result was 0.15 below the significance threshold.

The median rPFS in the darolutamide arm was 5.5 months compared with 4.5 months in the placebo arm (HR, 0.54; 95% CI, 0.32-0.91; log-rank P =.017). In terms of EFS, the median observed in the darolutamide arm was 5.4 months versus 2.9 months with placebo (HR, 0.46; 95% CI, 0.29-0.73; log-rank P =.001). The median OS was 24.0 months with darolutamide compared with 21.3 months in the placebo arm (HR, 0.62; 95% CI, 0.3-1.26; log-rank P=.181).

Further efficacy results from SAKK 08/16 showed that PSA50 responses were achieved in 22% of the patients treated with darolutamide versus 4% of those treated with placebo (P =.014). Notably, 30% PSA response was observed in 31% versus 9%, respectively, and 90% PSA response was seen in 2% of the darolutamide arm. The median duration of PSA response observed with darolutamide was 7.7 months compared with 2.8 months in the placebo arm.

Cathomas also explain subgroup outcomes on darolutamide versus placebo during his presentation. “We did a subgroup analysis, evaluating rPFS and OS. According to the response to the latest NHA therapy for patients who had a CR or PR two prior abiraterone or enzalutamide, rPFS and OS were much better on darolutamide than on placebo, whereas this was not the case if the patients had only stable disease or progressive disease on the latest NHA therapy.”

The safety analysis showed that treatment-related AEs were mild, and occurrences were similar between the 2 treatment arms. In the darolutamide arm 26% of the event were grade 1 compared with 22% in the placebo arm. The most common treatment-related AE were grade 1 fatigue, and anorexia, which occurred in 11% of the darolutamide arm versus 20% in the placebo arm and 2% versus 4%, respectively.

Results from the SAKK 08/16 trial provide proof of concept for immediate switch to darolutamide maintenance following taxane-based therapy with at least 1 NHA. Further, the data signal that response to NHA may be predictive of benefit from maintenance after NHA and taxane-based therapy in patients with mCRPC. According to Cathomas, the results are hypothesis-generating for a phase 3 clinical trial.


1. Cathomas R, Procopio G, Hayoz S, et al. Darolutamide maintenance in metastatic castration resistant prostate cancer (mCRPC) previously treated with novel hormonal agents (NHA) and non-progressive disease after subsequent treatment with a taxane: A randomized double-blind placebo-controlled phase II trial (SAKK 08/16). Presented at: 2021 European Society for Medical Oncology Congress. September 16-21, 2021. Abstract LBA26.