Darolutamide Maintenance Improves Outcomes in Patients with mCRPC Who Were Previously Treated with an ARPI, and Not Progressing After Subsequent Taxane Treatment

SAKK 08/16 is the first study to demonstrate the efficacy and safety of darolutamide in metastatic castration-resistant prostate cancer (mCRPC). In this study, darolutamide improved radiographic progression-free survival (rPFS), event-free survival (EFS), and prostate-specific antigen (PSA) 50% response rate compared with placebo without increasing adverse events in patients with mCRPC who had at least stable disease under taxane chemotherapy and who had previously received an androgen-receptor pathway inhibitor (ARPI). The most marked response was observed in those patients who had responded to prior ARPI therapy. This may represent a new treatment strategy for selected patients. A non-toxic maintenance treatment prolonging the achieved disease control would likely be useful to prevent progression-related symptomatic events while maintaining patients’ quality-of-life (QoL). The study findings are published by Prof. Silke Gillessen of the EOC—Istituto Oncologico della Svizzera Italiana in Bellinzona and Faculty of Biomedical Sciences, USI in Lugano, Switzerland and colleagues on 7 February 2023 in the Journal of Clinical Oncology.

The authors wrote in the background that both docetaxel and ARPIs (abiraterone and enzalutamide) are associated with improved overall survival (OS) as first-line treatment in patients with mCRPC who had previously received androgen-deprivation therapy (ADT) alone for metastatic hormone-sensitive prostate cancer (mHSPC). Abiraterone and enzalutamide improved OS in patients with progressive mCRPC after docetaxel, whereas no studies prospectively evaluated docetaxel in patients with mCRPC previously treated with ARPI. Most patients who are fit for chemotherapy receive ARPI as first-line treatment for mHSPC or patients with mCRPC subsequently receive docetaxel. Cabazitaxel improves OS in patients with mCRPC progressing either on or after docetaxel, and in patients with mCRPC previously treated with docetaxel and ARPIs. Olaparib and 177Lu-PSMA-617 improve OS in patients with progressive mCRPC after at least one ARPI. In patients with mCRPC responding to taxane, no immediate treatment is administered, with patients simply followed-up.

Since 2004, several treatments have been shown to improve OS in mCRPC, but in this crowded therapeutic scenario, the optimal sequence of these therapies has not yet been established. Although ARPIs are usually continued until progression or unacceptable toxicity, taxane chemotherapies are only performed up to a maximum number of cycles, after which patients without progression are simply being followed-up, continuing ADT alone. Usually, the time to progression after ending taxane treatment is only a few months. For this reason, a non-toxic maintenance treatment prolonging the achieved disease control would likely be useful to prevent progression-related symptomatic events while maintaining patients’ QoL. 

SAKK reported previously the results from a randomised study that switches maintenance with orteronel in patients with mCRPC after docetaxel chemotherapy was beneficial and feasible with a significantly improved EFS. In a phase II study, tasquinimod maintenance resulted in a statistically significant improved rPFS compared with placebo, but with relevant toxicity. Darolutamide is an ARPI with a distinctly different structure than enzalutamide and apalutamide. Darolutamide demonstrated a significant OS benefit in patients with non-mCRPC and, recently, in the mHSPC setting, with a maintained QoL. Darolutamide displays a favourable safety profile with only few drug-drug interactions and is therefore an ideal candidate for maintenance treatment. Despite the cross-resistance between different ARPIs, some data suggest that chemotherapy might reinduce sensitivity to ARPI.

SAKK 08/16 is a randomized phase II study in which patients with mCRPC who received prior ARPIs and subsequently had non-progressive disease on a taxane were randomly assigned to darolutamide 600 mg twice a day or placebo twice a day. The primary endpoint was rPFS at 12 weeks. Secondary endpoints were rPFS, EFS, OS, PSA 50% response rate, and adverse events. Overall, 92 patients were recruited by 26 centers. Prior taxane was docetaxel in 93% and cabazitaxel in 7% of patients. Prior ARPI was abiraterone in 60%, enzalutamide in 31%, and both in 9% of patients.

rPFS at 12 weeks was significantly improved with darolutamide (64.7% versus 52.2%; p = 0.127). Median rPFS on darolutamide was 5.5 versus 4.5 months on placebo (hazard ratio [HR] 0.54; 95% confidence interval [CI] 0.32 to 0.91; p = 0.017), and median EFS was 5.4 versus 2.9 months (HR 0.46; 95% CI 0.29 to 0.73; p = 0.001). PSA 50% response rate was improved (22% versus 4%; p = 0.014). Median OS for darolutamide was 24 versus 21.3 months for placebo (HR 0.62; 95% CI 0.3 to 1.26; p = 0.181). Treatment-related adverse events were similar in both arms.

The authors concluded that SAKK 08/16 met its primary endpoint, showing that switch maintenance with darolutamide after prior taxane chemotherapy and at least one ARPI resulted in a statistically significant, but clinically modest rPFS prolongation with good tolerability. The median OS with darolutamide maintenance appears promising. Should these findings be confirmed in a larger trial, maintenance treatment could be a novel strategy in managing patients with mCRPC, especially those who responded well to prior ARPI.

The study was previously presented at the ESMO 2021 Congress in Paris, France.

The study was supported by and investigational study drug provided by Bayer HealthCare Pharmaceuticals Inc.


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). JCO; Published online 8 February 2023. DOI: 10.1200/JCO.22.01726