Switch Maintenance Darolutamide Prolongs rPFS in Metastatic Prostate Cancer

Switch maintenance therapy with darolutamide (Nubeqa) yielded a statistically significant yet clinically modest prolonged radiographic progression-free survival (rPFS) following treatment with at least 1 androgen receptor pathway inhibitor and taxane chemotherapy in a cohort of patients with metastatic castration-resistant prostate cancer (mCRPC), according to data from the phase 2 SAKK 08/16 trial (NCT02933801) published recently in the Journal of Clinical Oncology.

"To our knowledge, SAKK 08/16 is the first trial to demonstrate the efficacy and safety of darolutamide in the mCRPC setting," according to the investigators of the phase 2 SAKK 08/16 trial.

The rPFS rate at 12 weeks was 64.7% (95% CI, 47.6%-77.5%) with darolutamide and 52.2% (95% CI, 36.1%-66.1%) with placebo (P = .127). Median rPFS was 5.5 vs 4.5 months with darolutamide and placebo, respectively (HR, 0.54; 95% CI, 0.32-0.91; P = .017), and median event-free survival (EFS) was 5.4 vs 2.9 months (HR, 0.46; 95% CI, 0.29-0.73; P = .001).

Median overall survival (OS) among those receiving darolutamide was 24.0 months vs 21.3 month among those receiving placebo (HR, 0.62; 95% CI, 0.3-1.26; P = .181). Investigators also reported a prostate-specific antigen (PSA) response rate of 50% in 22% of those in the experimental arm vs 4% with placebo (P = .014).

“To our knowledge, SAKK 08/16 is the first trial to demonstrate the efficacy and safety of darolutamide in the mCRPC setting,” the investigators said. “Darolutamide maintenance may represent a new therapeutic strategy in patients with mCRPC with at least stable disease under taxane, especially in those with partial or complete radiologic response to the latest androgen receptor pathway….”

From April 20, 2017 to November 19, 2020, this double-blind, randomized, controlled clinical trial assessed outcomes in 90 patients from 23 centers in France, Italy, Spain, and Switzerland. Patients most commonly had bone metastases (86.7% vs 88.9%) in both the darolutamide and placebo groups. The most common previously received taxane among patients in the darolutamide and placebo groups, respectively, was docetaxel (95.6% vs 86.7%) and abiraterone was the most common prior androgen-receptor pathway inhibitor (60.0% vs 60.0%).

The median age was 71 years old (range, 56-81) in the experimental group and 72 years old (55-87) in the placebo group. Most patients in each respective arm had stable disease as the best response following their last chemotherapy (68.9% vs 53.3%), with the remainder achieving a partial response (28.9% vs 42.2%) or complete response (2.2% vs 4.4%).

Patients were randomly assigned 1:1 to either the experimental (n = 45) or control (n = 45) group. They received best supportive care plus either darolutamide at 600 mg twice daily or a matched placebo. Treatment was required to begin within 2 to 8 weeks following the patient’s last chemotherapy dose.

Investigators additionally reported that the time to PSA progression was 2.7 months with darolutamide vs 1.9 months with placebo (HR, 0.48; 95% CI, 0.30-0.77; P = .001). The median duration of PSA response of 50% was 7.7 vs 2.8 months with darolutamide and placebo, respectively, and time to symptomatic/clinical progression was 8.7 vs 5.7 months (HR, 0.67; 95% CI, 0.37-1.23; P = .197).

Moreover, a subgroup analysis examining patients with a complete or partial radiologic response to their latest androgen-receptor pathway inhibitor (n = 29) found that darolutamide significantly prolonged rPFS (HR, 0.35; 95% CI, 0.14-0.87; P = .019) and OS (HR, 0.26; 95% CI, 0.06-1.19; P = .063). Investigators did not observe a significant difference in outcomes between patients with stable (HR, 0.7; 95% CI, 0.36-1.35; P = .28) or progressive disease (HR, 0.97; 95% CI, 0.39-2.43; P = .95) as their best response to prior androgen-receptor pathway inhibitor therapy.

A total of 26% and 22% of patients developed a grade 1 treatment-related adverse effect (TRAE) in the experimental and control groups, respectively. The incidence of grade 2 TRAEs was 13% and 15%, respectively, and the incidence of grade 3 TRAEs was 2% in both groups.

No grade 4 or 5 TRAEs affected patients in the darolutamide group, and 3 non–treatment-related deaths occurred in the placebo group. Fatigue, though less common in the experimental arm, was the most common TRAE across the study population.

“In addition to clinical features, molecular characterization could be useful in identifying patients who would most likely benefit from maintenance darolutamide therapy, but the molecular status of our study patients is unknown,” the investigators concluded. “[Nonetheless], darolutamide maintenance therapy compared with placebo improved clinical outcomes in [this] patient [population]…without increasing toxicity. The most marked response was observed in those patients who had responded to prior [ androgen-receptor pathway inhibitor] therapy. This may represent a new treatment strategy for selected patients.”

Reference

Gillessen S, Procopio G, Hayoz S, et al. Darolutamide maintenance in patients with metastatic castration-resistant prostate cancer with nonprogressive disease after taxane treatment (SAKK 08/16). J Clin Oncol. Published online February 8, 2023. doi:10.1200/JCO.22.01726