Darolutamide Plus ADT/Docetaxel Elicits Survival Benefit Across Subgroups in mHSPC

The addition of darolutamide (Nubeqa) to androgen-deprivation therapy (ADT) and docetaxel prolonged overall survival (OS) in patients with metastatic hormone-sensitive prostate cancer (mHSPC), irrespective of disease volume or disease risk, and the combination should be considered the new standard of care for this patient population. Results from a posthoc analysis of the phase 3 ARASENS trial (NCT02799602) were presented at the 2023 American Society of Clinical Oncology Genitourinary Cancers Symposium and simultaneously published in the Journal of Clinical Oncology.^1,2

Darolutamide plus ADT and docetaxel reduced the risk of death by approximately 30% across all volume and risk subgroups. The median OS was not reached (NR; 95% CI, 50.3-NR) for those with high-volume disease who received darolutamide vs 42.2 months (95% CI, 39.7-46.0) for those who received placebo (HR, 0.69; 95% CI, 0.57-0.82). The median OS was NR in the darolutamide arm or the placebo arm for those with low-volume disease (HR, 0.68; 95% CI, 0.41-1.13).^1,2

Median overall survival was also NR with darolutamide in the high-risk disease subgroup vs 43.2 months (95% CI, 40.0-48.9) with placebo/ADT/docetaxel (HR, 0.71; 95% CI, 0.58-0.86). Among those with low-risk disease the median OS was NR in either arm (HR, 0.62; 95% CI, 0.42-0.90).

“The HR for both the low-volume and the high-volume [subgroups] favored the triplet therapy,” Maha H.A. Hussain, MD, FASCO, FACP, said in a presentation of the data. “I want to point out, the median OS is not reached in both categories [with darolutamide]. One of the issues is with low-volume [disease], the HR slightly crosses 1. However, I want to point out that both this is a generally favorable group of patients, the medians have not been reached yet, and there is some separation in the curves later, so it’ll be interesting to see as we do more follow-up if there’s different signals.” Hussain is the Genevieve Teuton Professor of Medicine in the Division of Hematology-Oncology, Department of Medicine, and the deputy director and leader of the Genitourinary Oncology Program at the Robert H. Lurie Comprehensive Cancer Center of the Northwestern University Feinberg School of Medicine in Chicago, Illinois.

“We conclude that darolutamide with ADT and docetaxel should be considered a new standard of care for patients with mHSPC,” Hussain said.

Metastatic presentation, disease volume, and risk status have been used as prognostic factors for patients with mHSPC. The analysis aimed to analyze outcomes of these subgroups treated in ARASENS using the definition of disease burden defined in CHAARTED (NCT00309985), which assessed ADT plus docetaxel, and risk status as defined in LATITUDE (NCT01715285), which assessed the addition of an androgen receptor pathway inhibitor to ADT.²

The full analysis included 1305 patients, 1005 (77%) had high-volume disease, 912 (70%) had high-risk disease, 300 (23%) had low-volume disease and 393 (30%) had low-risk disease.^1,2

High-volume disease was defined using the CHAARTED criteria, which included visceral metastases and/or at least 4 bone metastases with at least 1 extending beyond the vertebral column or pelvis. High-risk disease was defined using the LATITUDE criteria with patients having to have at least 2 of the following risk factors: Gleason score 8 or higher, at least 3 bone lesions, and presence of measurable visceral metastasis. Of note, over 80% of patients had de novo metastatic disease.^1,2

Patients were randomly assigned 1:1 to 600 mg of darolutamide twice daily or placebo, in combination with ADT. Docetaxel was administered for 6 cycles in both arms.^1,2

Prior research showed that darolutamide plus ADT and docetaxel significantly reduced the risk of death by 32% (HR, 0.68; 95% CI, 0.57-0.80; P < .001), compared with placebo in patients with mHSPC.³

The median time to castration-resistant prostate cancer (CRPC) was NR (95% CI, 41.5-NR) among those with high-volume disease who received darolutamide combination compared with 16.4 months (95% CI, 13.9-19.3) with placebo (HR, 0.41; 95% CI, 0.34-0.49). The median time to CRPC was also NR among those with low-volume disease who received darolutamide vs 25.8 months for those who received placebo (HR, 0.21; 95% CI, 0.14-0.33).

The addition of darolutamide was beneficial across all key secondary end points. Among all treated patients, the median time to pain progression (HR, 0.79; 95% CI, 0.66-0.95), median time to first symptomatic skeletal event (HR, 0.71; 95% CI, 0.54-0.94), and median time to initiation of subsequent systemic antineoplastic therapy (HR, 0.39; 95% CI, 0.33-0.46) were all improved with darolutamide vs placebo.

These findings were consistent across subgroup analyses. For those with high-volume disease, darolutamide improved the median time to pain progression (HR, 0.75; 95% CI, 0.61-0.93), time to first symptomatic skeletal event (HR, 0.71; 95% CI, 0.53-0.96), and time to initiation of subsequent systemic antineoplastic therapy (HR, 0.40; 95% CI, 0.34-0.49). For those with low-volume disease, the median time to pain progression (HR, 0.94; 95% CI, 0.66-1.36) and time to first symptomatic skeletal event (HR, 0.89; 95% CI, 0.40-1.95) were least improved with darolutamide vs placebo; however, those with low-volume disease saw the greatest improvement in median time to initiation of subsequent systemic antineoplastic therapy (HR, 0.34; 95% CI, 0.22-0.52).

For those with high-risk disease the HR also favored darolutamide vs placebo for time to pain progression (HR, 0.81; 95% CI, 0.65-1.01), time to first symptomatic skeletal event (HR, 0.84; 95% CI, 0.61-1.15), and time to initiation of subsequent systemic antineoplastic therapy (HR, 0.40; 95% CI, 0.33-0.48). For those with low-risk disease, the HRs were 0.76 (95% CI, 0.55-1.06), 0.46 (95% CI, 0.25-0.84), and 0.36 (95% CI, 0.26-0.52), respectively.

“All of these are important secondary end points,” Hussain said. “And what you see here, irrespective of the risk criteria or the volume of disease, the triplet had a better outcome [with] the HRs favoring the triplet therapy.”

Incidence of treatment-emergent adverse events (TEAEs) were consistent with the overall population across subgroups by high-/low-volume and high-/low-risk and were consistent across treatment arms. For those with high-volume disease who received darolutamide (n = 498) grade 3 TEAEs occurred in 37.8% of patients, grade 4 TEAEs occurred in 27.1% of patients, and grade 5 TEAEs occurred in 4.2% of patients. These rates were 37.4%, 26.9%, and 4.0%, respectively in the placebo arm (n = 506). The rate of discontinuation of darolutamide was 13.3% and rate of discontinuation of placebo was 10.7%. The rates of discontinuation for docetaxel were 7.8% and 10.7%, respectively.

For those with low-volume disease who received darolutamide (n = 154) the rate of grade 3, 4, and 5 TEAEs was 39.0%, 31.2%, and 3.9%, respectively. For those who received placebo, the rates were 29.9%, 31.3%, and 4.2%, respectively. In this subgroup, the rate of discontinuation of darolutamide was 14.3% and rate of discontinuation of placebo was 10.4%. The rates of discontinuation for docetaxel were 8.4% and 9.0%, respectively.

TEAEs of grade 3, 4, and 5 occurred in 37.3%, 30.2%, and 3.8% of patients with high-risk disease in the darolutamide arm (n = 453) and in 36.5%, 27.8%, and 4.2% of patients, respectively, in the placebo arm (n = 457). Discontinuation of darolutamide was reported for 12.8% of patients and 9.8% of patients discontinued placebo. The rates of docetaxel discontinuation in this subgroup were 8.4% and 9.8% in the experimental and control arms, respectively.

Finally, for patients with low-risk disease, the rate of grade 3, 4, and 5 TEAEs for patients who received darolutamide (n = 199) were 37.9%, 23.1%, and 5.0%, respectively. For those who received placebo (n = 193), the incidence of grade 3, 4, and 5 TEAEs was 33.7%, 28.0%, and 3.6%, respectively. The rate of darolutamide discontinuation was 15.1% and the rate of placebo discontinuation was 12.4%. Rates of docetaxel discontinuation were 7.0% and 11.4%, respectively. 

“The favorable safety profile of darolutamide was confirmed in all volume and risk populations [and was] consistent with the data that was reported in the overall population of this study,” Hussain said.

References

1. Hussain M, Tombal BF, Saad F, et al. Efficacy and safety of darolutamide (DARO) in combination with androgen-deprivation therapy (ADT) and docetaxel (DOC) by disease volume and disease risk in the phase 3 ARASENS study. J Clin Oncol. 2023;41(suppl 6):15. doi:10.1200/JCO.2023.41.6_suppl.15
2. Hussain M, Tombal BF, Saad F, et al. Darolutamide plus androgen-deprivation therapy and docetaxel in metastatic hormone-sensitive prostate cancer by disease volume and risk subgroups in the phase III ARASENS trial. J Clin Oncol. Published online February 16, 2023. doi:10.1200/JCO.23.00041
3. Smith MR, Hussain M, Saad F, et al; ARASENS Trial Investigators. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. N Engl J Med. 2022;386(12):1132-1142. doi:10.1056/NEJMoa2119115