Addition of darolutamide to androgen deprivation therapy significantly prolongs overall survival in men with non-metastatic castration-resistant prostate cancer

In the phase III ARAMIS trial, darolutamide plus androgen deprivation therapy (ADT) was compared to placebo + ADT in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) with a prostate-specific antigen doubling time (PSA DT) of 10 months or less. In the primary analysis of this trial, darolutamide was shown to significantly prolong the metastasis-free survival (MFS) compared to placebo, with a 22 months difference in median MFS. The pre-specified final analysis of the ARAMIS, presented at ASCO 2020, demonstrated that the addition of darolutamide to ADT also led to a significantly longer overall survival (OS). Furthermore, darolutamide provided additional clinical benefits over placebo by significantly delaying the onset of cancer-associated morbidity and subsequent chemotherapy.

Introduction

Non-metastatic CRPC is defined as having a rising PSA level despite castrate levels of testosterone with ongoing ADT in the absence of detectable metastases on conventional imaging. Patients with nmCRPC are at risk of metastatic progression and cancer-specific mortality and morbidity. As the nmCRPC patient population is largely asymptomatic and still active in daily life, they would benefit from treatments that prolong their survival and delay disease progression without the burden of treatment-related adverse events and with a minimal impact on their quality of life. Darolutamide is a structurally distinct androgen receptor inhibitor (ARI) with a low blood-brain barrier penetration and a low potential for drug-drug interactions. In the phase III ARAMIS trial, darolutamide plus androgen deprivation therapy (ADT) was compared to placebo + ADT in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) with a prostate-specific antigen doubling time (PSA DT) of 10 months or less. The prespecified final analysis of the ARAMIS trial for OS, other secondary endpoints and long-term safety were reported at ASCO 2020.

In ARAMIS, 1509 men with nmCRPC and a PSA DT of ten months or less were randomised (2:1) to receive darolutamide 600 mg, twice daily or placebo, while continuing ADT. The study was unblinded following positive results of the primary analysis, at which time patients in the placebo group were allowed to cross-over to open-label darolutamide or to receive subsequent therapy at the discretion of the investigator. A total number of 170 patients crossed over to darolutamide. Secondary endpoints (overall survival, time to pain progression, time to first cytotoxic chemotherapy and time to first symptomatic skeletal event) were tested hierarchically for significance.

Results

Darolutamide was associated with a statistically significant 31% reduction in the risk of death compared to placebo (HR [95%CI]: 0.69 [0.53-0.88], p=0.003). After a median follow-up of 29.1 months, the OS rate at three years was 83% for patients in the darolutamide arm, as compared to 77% for patients in the placebo arm. This OS benefit was observed despite the fact that half of the patients in the placebo group (56%) received subsequent darolutamide or another life-prolonging therapy. Darolutamide also significantly delayed the time to pain progression from 25.4 months in the placebo-ADT arm to 40.3 months in the darolutamide-ADT arm (HR [95%CI]: 0.65 [0.53-0.79], p < 0.001). In addition, also the time to first cytotoxic chemotherapy and the time to first symptomatic skeletal event were significantly delayed (HR [95%CI]: 0.58 [0.44-0.76], p<0.001 and HR [95%CI]: 0.48 [0.29-0.82], p=0.005 respectively) with darolutamide + ADT. As such, darolutamide provides clinical benefits, in addition to prolonging survival, in men with nmCRPC for whom the development of metastases can cause cancer-related symptoms that affect their daily life or impose the burden of additional treatments.

The safety profile of darolutamide was consistent with that of the primary analysis. After adjustment for treatment exposure, incidences of key adverse events, known to be associated with androgen receptor inhibition, continue to show small or no differences between both groups. However, the incidence of cardiac arrhythmias was higher in the darolutamide arm (7.3%) compared to the placebo arm (4.3%). In this respect, it is important to note that both a medical history of cardiac arrhythmia and baseline electrocardiogram abnormalities were more common in the darolutamide-ADT arm. Of note, also patients with a history of epilepsy were allowed to enter the trial and the incidence of seizures was exactly the same (0.2%) in both study arms.

Conclusions

Adding darolutamide to ADT significantly improved the OS in men with nmCRPC. In addition, darolutamide provides additional clinical benefits by significantly delaying the onset of cancer-associated morbidity and subsequent chemotherapy versus placebo. With extended follow-up, the safety profile of darolutamide was favourable and consistent with the primary analysis reported. These results provide further evidence for the use of darolutamide in men with nmCRPC.

Reference

Fizazi K, Shore ND, Tammela T, et al. Overall survival (OS) results of phase III ARAMIS study of darolutamide (DARO) added to androgen deprivation therapy (ADT) for nonmetastatic castration-resistant prostate cancer (nmCRPC). Presented at ASCO 2020; Abstract 5514.