Efficacy and safety of darolutamide in Black/African–American patients from the phase III ARAMIS study

Prostate cancer is the most common cancer in men in the USA and the second most common behind lung cancer globally [1,2]. Prostate cancer accounts for 11 and 7% of cancer-related deaths in the USA and worldwide, respectively [1,2]. Black and African–American patients have higher incidence rates of prostate cancer and are more likely to die from prostate cancer compared with patients from other racial and ethnic groups [1,3]. In the USA, prostate cancer incidence rates from 2014 to 2018 were 172.6 per 100,000 in non-Hispanic Black patients compared with 99.9 per 100,000 for non-Hispanic White patients and 85.3 per 100,000 for Hispanic patients [4]. Similarly, mortality rates from 2015 to 2019 were higher among non-Hispanic Black patients (37.9 per 100,000) compared with non-Hispanic White patients (17.8 per 100,000) and Hispanic patients (15.6 per 100,000). Globally, incidence rates of prostate cancer for African–American patients, Caribbean patients and Black patients in Europe are among the highest in the world [3].

The disparity in prostate cancer outcomes by race has been attributed to many factors including hormone levels, diet, genetic and molecular alterations, cancer treatment and screening and access to healthcare [5–7]. At the time of prostate cancer diagnosis, Black/African–American patients are more likely to be younger and have higher prostate-specific antigen (PSA) levels and Gleason scores, more extensive disease, and a worse performance status compared with White or European/American patients [5,8–10]. Black/African–American patients with prostate cancer also exhibit a high frequency of mutations in key prostate cancer drivers and differential gene expression associated with more aggressive disease [10–16]. Despite these potentially negative predictive factors, Black/African–American patients are less likely to receive treatment and experience a longer delay in receiving primary treatment compared with White patients [9,17]. Research suggests that when disparities in access to care and known prognostic factors are controlled, Black/African–American patients have similar or better outcomes compared with White patients [18]. In a noncomparative, open-label trial of abiraterone plus prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC), Black (n = 50) and White (n = 50) patients had similar rates of progression-free survival and overall survival [19].

Darolutamide is a highly potent and structurally distinct androgen receptor inhibitor (ARi) that has low blood–brain barrier penetration and limited potential for drug–drug interactions [20–22]. In the randomized, controlled, phase III ARAMIS study of patients with nonmetastatic castration-resistant prostate cancer (nmCRPC), darolutamide significantly improved metastasis-free survival (MFS) compared with placebo, with a median MFS of 40.4 versus 18.4 months, respectively (hazard ratio [HR] 0.41, 95% CI 0.34, 0.50; p < 0.001) [23]. In the final analysis of the study, darolutamide significantly reduced the risk of death by 31% compared with placebo (HR 0.69, 95% CI 0.53, 0.88; p = 0.003), and 3-year survival rates were 83% for darolutamide versus 77% for placebo [24]. Darolutamide has a consistently favorable safety profile. Most adverse events commonly associated with ARis showed ≤2% difference between darolutamide and placebo. Fatigue was the only adverse event with an incidence >10% in the darolutamide arm (13.2 vs 8.3% in the placebo arm). Similar proportions of patients discontinued treatment due to adverse events in the darolutamide group (8.9%) and in the placebo group (8.7%) [24]. We report results from a subgroup analysis of the efficacy and safety of darolutamide in Black/African–American patients from ARAMIS.

Patients & methods

Study design & patients

ARAMIS was a phase III, randomized, double-blind, global, multicenter study of darolutamide versus placebo plus androgen-deprivation therapy (ADT) in patients with nmCRPC (NCT02200614). The methods of the study have been previously reported [23,24] and are briefly summarized. Patients aged 18 years and older with histologically or cytologically confirmed prostate adenocarcinoma were eligible for the study if they had a baseline PSA ≥2 ng/ml, PSA doubling time of ≤10 months, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were excluded if they had a history of metastatic disease or evidence of metastases on imaging.

The study was approved by the institutional review board at each participating institution and was conducted in accordance with principles of the Declaration of Helsinki and the International Conference on Harmonisation guidelines for GCP. All patients provided written informed consent to participate.

Eligible patients were randomly assigned 2:1 to oral darolutamide 600 mg twice daily or matched placebo, while continuing ADT. Randomization was stratified by PSA doubling time (≤6 months or >6 months) and the use of osteoclast-targeted therapy (yes vs no). Patients continued treatment until protocol-defined progression, intolerable adverse events or withdrawal of consent.

Study end points

The primary end point of the study was MFS, defined as the time from randomization to confirmed evidence of distant metastasis on imaging or death from any cause, whichever occurred first. Secondary and exploratory end points included overall survival (OS); time-to-pain progression, defined as either an increase of ≥2 points from baseline on the Brief Pain Inventory Short Form questionnaire or initiation of opioid treatment for cancer pain; time to first symptomatic skeletal event, defined as external-beam radiation therapy to relieve skeletal symptoms, new symptomatic pathologic bone fracture, spinal cord compression, or tumor-related orthopedic surgical intervention; time to the use of first cytotoxic chemotherapy; and time to PSA progression. Safety was evaluated in all patients who underwent randomization and received ≥1 dose of study treatment. Data were collected on adverse events, including type, severity, and seriousness. Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

Statistical analyses

Post hoc analyses of the Black/African–American subgroup were performed using Kaplan–Meier estimates to compute medians and 95% CIs. Cox regression model without stratification was used to calculate HRs and 95% CIs for comparison between treatment arms. If HR could not be calculated, an ad hoc analysis estimated the odds ratio of events using Fisher's exact test.

Results

Patients

Fifty-two Black/African–American patients received darolutamide (n = 28) or placebo (n = 24) in ARAMIS. Overall, Black/African–American patients represented 3.4% of the ARAMIS population with the following geographic distribution: United States (25 of 290 [8.6%]), Brazil (21 of 230 [9.1%]), France (3 of 118 [2.5%]), Canada (1 of 71 [1.4%]), Sweden (1 of 47 [2.1%]) and Portugal (1 of 68 (1.5%]). Demographic and baseline characteristics were generally consistent with the overall ARAMIS population with a few notable differences (Table 1). Black/African–American patients treated with darolutamide had a median time from diagnosis of 101 months and 50% (n = 14) had an ECOG performance status of 1 compared with 86 months and 32%, respectively, in the overall ARAMIS population [23]. Among patients who received placebo, the median time from diagnosis was 128 months for Black/African–American and 84 months for all patients, and ECOG performance status of 1 was reported for 29% in both populations. Regarding prior primary therapy for prostate cancer, radiotherapy was used more frequently in Black/African–American patients compared with all patients (darolutamide: 43 and 19%; placebo: 33 and 16%, respectively) and rates of prior prostatectomy were similar between populations (darolutamide: 21 and 25%; placebo: 29 and 24%) (Table 1).

Efficacy

At the primary analysis data cut-off (3 September 2018), darolutamide improved MFS compared with placebo in Black/African–American patients. The median was not reached in the darolutamide group and was 12.4 months in the placebo group, with one event and ten events per treatment group, respectively (Figure 1). By the time the only event occurred in the darolutamide group, all placebo patients had discontinued the trial, and HR could not be calculated. At the final analysis data cut-off (15 November 2019), darolutamide showed an OS benefit compared with placebo (one death vs seven deaths, respectively; HR 0.09; 95% CI 0.01-0.72) that was consistent with the overall population, and the median OS was not reached in either group (Figure 2). Three-year OS rates were 100% for darolutamide versus 71% for placebo.

For evaluable secondary efficacy end points, darolutamide showed a longer time to first cytotoxic chemotherapy and median time to PSA progression compared with placebo (Table 2). There were no symptomatic skeletal events in Black/African–American patients and time-to-pain progression was not evaluable due to the low number of events in the Black/African–American population.

Safety

The safety profile of darolutamide in Black/African–American patients was consistent with that observed for all patients in the ARAMIS study (Table 3). In Black/African–American patients treated with darolutamide versus placebo, fewer adverse events (82 vs 92%) and discontinuations due to adverse events (4 vs 17%) were reported. Rates of grade 3/4 adverse events in Black/African–American patients were higher in the darolutamide group (25%) compared with the placebo group (8%), but the rate was consistent with that of the overall population (darolutamide, 26% vs placebo, 22%, respectively). Adverse events commonly associated with ARis including falls, fractures, hypertension, rash, mental impairment and fatigue followed similar trends in the Black/African–American patients as observed in the overall population (Table 3).

Discussion

In the USA and Brazil, approximately 9% of patients enrolled in the ARAMIS trial were Black/African–American, with smaller proportions of Black patients from Canada and European countries. In this subgroup analysis of ARAMIS, Black/African–American patients with nmCRPC showed benefits that were consistent with those observed in the overall study population. Some baseline differences were observed in the Black/African–American population compared with the overall study population. Black/African–American patients had a longer median time from initial diagnosis to study treatment compared with the overall population by 15 months in those receiving darolutamide and 44 months in those receiving placebo. Differences in the proportion of patients with an ECOG performance status of 1 were observed for the Black/African–American patients receiving darolutamide (50 vs 32% for the overall population) but not for those receiving placebo (29% in both populations). Several studies have shown that Black/African–American patients present with more advanced prostate cancer compared with White or European/American patients [5,8–10], findings that may be related to differences in healthcare access, cancer screening, and diagnosis among the Black/African–American population [5,6,8]. An analysis of data from the US Veterans Affairs (VA) healthcare system found similar rates of death from prostate cancer for African–American and non-Hispanic White patients when healthcare access was equal, despite the fact that African Americans were more likely to live in lower income areas and have higher rates of comorbidity [25]. Another analysis of the VA system found that Black/African–American patients who received definitive treatment, particularly radiotherapy, had a significant improvement in distant metastasis compared with White patients [9]. These findings suggest that timely diagnosis and equitable treatment delivery are key factors in reducing racial disparities in prostate cancer outcomes.

In Black/African–American patients with nmCRPC, darolutamide was associated with improvements in MFS, OS, and patient-relevant end points, including the time to first cytotoxic chemotherapy and time to PSA progression, compared with placebo. No symptomatic skeletal events were reported in this subgroup of the ARAMIS population. Darolutamide was well tolerated in Black/African–American patients. Both the efficacy and safety profiles of darolutamide in Black/African–American patients were consistent with the overall ARAMIS study population [23,24].

Limitations of this analysis include the post hoc design and small number of Black/African–American patients that were included in the ARAMIS study. Treatment comparisons did not account for stratification factors or other confounders. Recruitment of Black/African–American patients with prostate cancer for enrollment into clinical trials has been historically poor [7,26]. Prostate cancer clinical trials have either failed to publish demographic information on race and ethnicity or included only a small proportion (<10%) of Black/African–American patients. Reasons for these disparities are beyond the scope of this paper, but they may include complex factors related to social injustices and systemic inequalities faced by the Black/African–American population, leading to mistrust in the healthcare system that deters research participation [7]. Consistent with the low recruitment observed in prostate cancer trials in general, few studies have evaluated new hormonal therapies, such as darolutamide and other ARis, in Black/African–American patients, particularly those with nmCRPC [26]. Interestingly, differences observed in survival outcomes are especially noted for Black/African–American patients with nonmetastatic or localized/regional prostate cancer as compared with metastatic disease [8,27].

This is the first report of treatment with an ARi in Black/African–American patients with nmCRPC and it supports the efficacy and safety of darolutamide in this population. Additional studies are needed to determine if androgen receptor mutations lead to differential treatment effects of ARis. In addition, alterations in prostate cancer genes in Black/African–American patients may reflect differences in disease biology that contribute to more advanced disease at presentation and poorer outcomes compared with other racial and ethnic groups [11–15]. These factors highlight the need for future clinical trial enhancement with both Black/African–American and other underrepresented racial/ethnic populations. Improving participation in clinical trials among Black/African–American patients will likely require efforts to build trust in the healthcare system within the community, utilize patient advocates, and increase awareness and educational opportunities [7]. Specific recommendations may include monetary incentives for participation, diversified research teams, and community-based recruiting tactics.

Conclusion

This analysis provides important information on the treatment outcomes of darolutamide in Black/African–American patients with nmCRPC. Darolutamide was associated with an improvement in MFS and OS and was well tolerated in this subgroup. These results were consistent with those of the overall ARAMIS population.