Darolutamide Combination Improves OS vs Placebo in Black Patients With mHSPC

Neal D. Shore, MD, FACS

Darolutamide (Nubeqa) plus androgen-deprivation therapy (ADT) and docetaxel elicited an overall survival (OS) benefit over placebo plus ADT and docetaxel in Black and African American patients with metastatic hormone-sensitive prostate cancer (mHSPC) similar to the benefit observed in the overall population of the phase 3 ARASENS trial (NCT02799602).¹

According to findings from a subgroup analysis of the study presented at the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved, the 4-year OS rate for patients who received the darolutamide combination was 61.7% in the Black/African American patient subgroup compared with 40.9% for those who received placebo. The median OS was not estimable [NE] in the experimental arm (95% CI, 47.2-NE) vs 38.7 months (95% CI, 29.2-NE) in the placebo arm (HR, 0.41; 95% CI, 0.17-1.02).

In the overall study population, the median OS was not estimable (NE; 95% CI, NE-NE) in the darolutamide arm vs 48.9 months (95% CI, 44.4-NE). The OS rate was 62.7% vs 50.4%, respectively, (HR, 0.68; 95% CI, 0.57-0.80; P <.0001).

“In this small population of Black/African-American patients with mHSPC from the ARASENS trial, darolutamide was associated with an improvement in OS and time to castration-resistant prostate cancer [CRPC],” Neal D. Shore, MD, FACS, of Carolina Urologic Research Center in Myrtle Beach, South Carolina, said in a presentation of the data.

The FDA approved the darolutamide/docetaxel/ADT combination for mHSPC in August 2022 based on previous findings from ARASENS. Those data showed the triplet induced a 32.5% reduced risk for death compared with docetaxel plus ADT.²

The randomized ARASENS trial investigated darolutamide, a potent androgen receptor inhibitor, plus ADT and docetaxel in 1306 patients with mHSPC. Prostate cancer disproportionately affects Black and African American patients, who experience higher incidence and mortality rates than other racial and ethnic groups. This subgroup analysis investigated the efficacy and safety of darolutamide plus ADT and docetaxel in Black and African American patients from ARASENS.

To be eligible for enrollment, patients needed to have mHSPC, an ECOG performance status (PS) of 0 or 1 and be candidates for ADT and docetaxel per the investigators’ discretion. Patients were stratified based on the metastatic extent of their disease (only nonregional lymph node metastases, bone metastases with or without lymph node metastases, and visceral metastases with or without lymph node or bone metastases) and whether their alkaline phosphate levels were below, at, or above the upper limit of normal.

Patients from 286 centers in 23 countries were randomly assigned standard docetaxel plus ADT with (n = 651) or without (n = 654) darolutamide at 600 mg twice daily.

The primary end point was OS. Secondary efficacy end points included time to CRPC, time to pain progression, symptomatic skeletal event–free survival, time to first symptomatic skeletal event, time to initiation of subsequent antineoplastic therapy, time to worsening of disease-related physical symptoms, time to initiation of opioid use for at least 7 consecutive days. Safety, another secondary end point, was assessed as treatment-emergent adverse effects (TEAEs).

In total, 54 Black and African American patients were randomized to ARASENS, 26 to the darolutamide arm and 28 to the placebo arm. The demographics and baseline characteristics of this subgroup were generally similar to those of the overall population.

However, the Black/African American subgroup had a lower median age, at 63.5 years (range, 52-84) and 63 years (range, 47-82) vs 67 years (range, 41-89) and 67 years (range, 42-86) in the overall population in the darolutamide and placebo arms, respectively. Additionally, a higher proportion of this subgroup had an ECOG PS of 1, at 42.3% (n = 11) and 32.1% (n = 9) vs 28.4% (n = 185) and 29.1% (n = 190) in the overall population in the darolutamide and placebo arms, respectively. Furthermore, more patients in the Black/African American subgroup had recurrent disease compared with the overall population.

Although the median prostate-specific antigen levels were similar between the subgroup and the overall population, the median alkaline phosphate levels were lower in Black and African American patients, at 113.5 (range, 59-1031) and 107 (range, 55-2065) vs 148 (range, 40-4885) and 140 (range, 36-7680) in the overall population in the darolutamide and placebo arms, respectively.

Data regarding time to CRPC from the Black/African American subgroup were consistent with that from the overall population. Specifically, in the subgroup, the median time to CRPC was NE (95% CI, NE-NE) in the darolutamide arm and 12.6 months (95% CI, 8.3-19.3) in the placebo arm (HR, 0.09; 95% CI, 0.02-0.30). In the overall population, the median time to CRPC was NE (95% CI, NE-NE) in the darolutamide arm and 19.1 months (95% CI, 16.5-21.8) in the placebo arm (HR, 0.36; 95% CI, 0.30-0.42; P <.001).

The median duration of treatment was longer for the darolutamide arm vs the placebo arm in both the subgroup (29.6 vs 12.4 months) and the overall population (41.0 vs 16.7 months).

The safety profile for the Black/African American patients was consistent with that for all patients. Grade 3/4 adverse effects (AEs) were observed in 61.5% (n = 16) and 60.7% (n = 17) of the subgroup vs 66.1% (n = 431) and 63.5% (n = 413) of the overall population in the darolutamide and placebo arms, respectively. Additionally, serious AEs occurred in 42.3% (n = 11) and 25.0% (n = 7) of the subgroup and 44.8% (n = 292) and 42.3% (n = 275) of the overall population in the darolutamide and placebo arms, respectively.

Moreover, darolutamide led to permanent treatment discontinuation in 19.2% (n = 5) and 14.3% (n = 4) of patients in the Black/African American subgroup and 13.5% (n = 88) and 10.6% (n = 69) of the overall population in the darolutamide and placebo arms, respectively.

In addition, the TEAEs associated with androgen receptor pathway inhibitors were similar between the 2 groups, and the TEAEs seen in the subgroup were generally consistent with those seen in the overall population. The investigators observed no new safety signals in this subgroup population.

Common TEAEs in the darolutamide and placebo arms of the subgroup and overall population, respectively, included fatigue (50.0% vs 53.6%; 33.1% vs 32.9%), vasodilation or flushing (30.8% vs 53.6%; 20.4% vs 21.7%), rash (7.7% vs 7.1%; 16.6% vs 13.5%), diabetes or hyperglycemia (15.4% vs 25.0%; 15.2% vs 14.3%), hypertension (30.8% vs 21.4%; 13.7% vs 9.2%), cardiac disorders (15.4% vs 10.7%; 10.9% vs 11.7%), bone fracture (7.7% vs 3.6%; 7.5% vs 5.1%), fall (15.4% vs 0%; 6.6% vs 4.6%), mental impairment disorders (3.8% vs 0%; 3.5% vs 2.3%), decreased weight (3.8% vs 10.7%; 3.4% vs 5.4%), depressed mood disorders (11.5% vs 7.1%; 3.2% vs 3.7%), and breast disorders or gynecomastia (0% vs 0%; 3.2% vs 1.5%).

“Efficacy and safety findings in Black and African-American [patients] were consistent with the overall ARASENS population. We strongly encourage all clinical research investigators, for both existing and future trials, to optimize racial and ethnic accrual,” Shore concluded.

References

1. Shore ND, Hussain MHA, Saad F, et al. Efficacy and safety of darolutamide in combination with androgen-deprivation therapy (ADT) and docetaxel in Black/African-American patients from the phase 3 ARASENS trial. Presented at: 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; September 16-19, 2022; Philadelphia, PA. Accessed October 27, 2022.
2. U.S. FDA approves additional indication of darolutamide in combination with docetaxel for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC). Orion Corporation. August 8, 2022. Accessed October 28, 2022. https://yhoo.it/3Niz3F5