ASCO GU 2023: Efficacy and Safety of Darolutamide in Combination with ADT and Docetaxel by Disease Volume and Disease Risk in the Phase 3 ARASENS Study

(UroToday.com) The 2023 GU ASCO annual meeting included a session on advanced prostate cancer, specifically new targets, new drugs, and new victories, featuring a presentation by Dr. Maha Hussain discussing efficacy and safety of darolutamide in combination with ADT and docetaxel by disease volume and disease risk in the phase 3 ARASENS study.

In ARASENS (NCT02799602), darolutamide plus ADT and docetaxel significantly reduced the risk of death by 32.5% (HR 0.68; 95% CI: 0.57–0.80) vs placebo + ADT + docetaxel in patients with metastatic hormone-sensitive prostate cancer, with similar overall incidences of treatment-emergent adverse events between groups.¹ The effect of darolutamide on overall survival was consistent across prespecified subgroups, including de novo and recurrent disease. For patients with metastatic hormone-sensitive prostate cancer, outcomes based on disease volume and risk provide additional information to clinicians. At the 2023 GU ASCO annual meeting, Dr. Hussain and colleagues presented a post-hoc analysis of the ARASENS study reporting the impact of disease burden and risk on efficacy and safety outcomes.

Patients with metastatic hormone-sensitive prostate cancer were randomized 1:1 to darolutamide 600 mg twice daily or placebo, with ADT + docetaxel. The trial design of ARASENS is as follows: 

High-volume disease was defined as visceral metastases and/or ≥4 bone metastases with ≥1 beyond the vertebral column/pelvis (CHAARTED criteria). High-risk disease was defined as ≥2 risk factors:

• Gleason score ≥8
• ≥3 bone lesions
• Presence of measurable visceral metastasis (LATITUDE criteria)

Overall survival for these subgroups was assessed using an unstratified Cox regression model.

 Of 1,305 patients in the full analysis set, 1,005 (77%) had high-volume disease, 912 (70%) had high-risk disease, 300 (23%) had low-volume disease, and 393 (30%) had low-risk disease. As follows is a table summarizing select baseline demographics and disease characteristics by disease volume:

And by disease risk:

Darolutamide + ADT + docetaxel prolonged overall survival regardless of high- or low-volume disease. Specifically, for high volume mHSPC (HR 0.69, 95% CI 0.57-0.82) and low volume mHSPC (HR 0.68, 95% CI 0.41-1.13):

And for high-risk mHSPC (HR 0.71, 95% CI 0.58-0.86) and low-risk mHSPC (HR 0.62, 95% CI 0.42-0.90):

Both high and low volume, and high and low risk disease, benefited from triplet therapy with regards to time to castration-resistant prostate cancer:

 
Darolutamide improved clinically relevant secondary endpoints vs placebo in high/low-volume and risk subgroups, with HRs generally in the range of those observed in the overall population:

Incidences of treatment-emergent adverse events were consistent with the overall ARASENS population across subgroups by high/low volume and high/low risk: 

Dr. Hussain concluded her presentation discussing efficacy and safety of darolutamide in combination with ADT and docetaxel by disease volume and disease risk in ARASENS with the following take-home messages:

• In patients with metastatic hormone-sensitive prostate cancer, the benefits of early treatment intensification with darolutamide + ADT + docetaxel on overall survival and key patient-relevant secondary efficacy endpoints vs placebo + ADT + docetaxel were similar in patients with high- and low-volume as well as high- and low-risk metastatic hormone-sensitive prostate cancer
• The favorable safety profile of darolutamide was reconfirmed in high/low-volume and high/low-risk populations
• Darolutamide + ADT + docetaxel sets a new standard of care for patients with metastatic hormone-sensitive prostate cancer

Presented by: Maha H. A. Hussain, MD, FACP, FASCO, Northwestern University, Feinberg School of Medicine, Chicago, IL

Co-Authors: Bertrand F. Tombal, Fred Saad, Karim Fizazi, Cora N. Sternberg, E. David Crawford, Neal D. Shore, Evgeny Kopyltsov, Arash Rezazadeh, Martin Boegemann, Ding-Wei Ye, Felipe Melo Cruz, Hiroyoshi Suzuki, Shivani Kapur, Shankar Srinivasan, Frank Verholen, Iris Kuss, Heikki Joensuu, Matthew Raymond Smith

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2023 Genitourinary (GU) American Society of Clinical Oncology (ASCO) Annual Meeting, San Francisco, Thurs, Feb 16 – Sat, Feb 18, 2023.

References:

1. Smith MR, Hussain M, Saad F, et al. Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer. N Engl J Med. 2022 Mar 24;386(12):1132-1142.