OS benefit with darolutamide maintained throughout mHSPC treatment course

In this interview, Neal Shore, MD, FACS, shares key findings from the study, “Overall survival with darolutamide vs placebo in combination with androgen-deprivation therapy (ADT) and docetaxel: A sensitivity analysis from ARASENS accounting for subsequent therapy,”¹ which was presented at the 2024 ASCO Genitourinary Cancers Symposium in San Francisco, California. Shore is the US chief medical officer of urology/surgical oncology at GenesisCare USA, as well as the director of the Carolina Urologic Research Center in Myrtle Beach, South Carolina.

Neal Shore, MD, FACS

Could you discuss the initial findings from the phase 3 ARASENS study?

Full results from the pivotal phase 3 ARASENS trial (NCT02799602), initially presented at ASCO GU 2022, demonstrated the potential of darolutamide (Nubeqa) plus ADT and docetaxel, completely shifting the treatment paradigm in metastatic hormone-sensitive prostate cancer (mHSPC).² These results were the first to show a successful combination of a novel androgen receptor inhibitor (ARi) with docetaxel.

The phase 3 ARASENS trial evaluating the oral ARi darolutamide in mHSPC met its primary end point and key secondary end points. Darolutamide plus ADT and docetaxel demonstrated a statistically significant increase in overall survival (OS), with a reduction in the risk of death by 32% compared with ADT plus docetaxel (HR, 0.68; 95% CI, 0.57-0.80; P < .001).

Additionally, the combination of darolutamide plus ADT and docetaxel also showed consistent benefits for secondary end points and pre-specified subgroups. Darolutamide plus ADT and docetaxel demonstrated a delay in time to castration-resistant prostate cancer, time to pain progression, time to first symptomatic skeletal event, and time to initiation of subsequent systemic antineoplastic therapy compared with ADT plus docetaxel. At the data cutoff date for the primary analysis (October 25, 2021), the median treatment duration was longer for darolutamide plus ADT and docetaxel (41.0 months) vs ADT plus docetaxel (16.7 months).

Based on results from the ARASENS trial, darolutamide plus ADT and docetaxel was approved in August 2022 as the first life-prolonging combination therapy approved for mHSPC. Results presented since continue to demonstrate that darolutamide plus ADT and docetaxel has a favorable tolerability profile and the ability to maintain patient quality-of-life with effective control of disease-related physical symptoms and pain–resulting in a strong efficacy and tolerability profile without compromise of quality of life.

Could you describe the background for the post hoc analysis of the study?

Prostate cancer patients can progress on any therapy, and often continue to subsequent therapies to continue in the treatment of disease in the face of progression. These post hoc analyses were designed to evaluate the impact of these subsequent therapies (referred to as informative intercurrent events) in patients who had received darolutamide as part of the phase 3 ARASENS trial. As part of this post hoc analysis, we counted initiation of subsequent chemotherapy as an event in censored patients who were alive at the end of follow-up.

What were the key findings from the analysis that were presented at ASCO GU?

Post-hoc sensitivity analyses from the phase 3 ARASENS trial presented at ASCO GU were consistent with and supportive of the ARASENS primary OS analysis–reinforcing darolutamide plus ADT plus docetaxel as an effective and well tolerated standard of care in patients with mHSPC.¹

What are the next steps for this study?

We will continue post-hoc analyses of relevant ARASENS outcomes as they relate to clinical practice. There is a broad development program for darolutamide underway, with darolutamide under investigation in various stages of prostate cancer. The ARANOTE trial (NCT04736199) is evaluating darolutamide plus ADT vs ADT alone in mHSPC outside the US, and the ARASTEP trial (NCT05794906) is evaluating darolutamide plus ADT vs ADT alone in HSPC patients with high-risk biochemical recurrence, no evidence of metastatic disease as measured by conventional imaging, and a positive PSMA PET/CT at baseline–looking at the potential of darolutamide in an earlier stage of the disease.

What are the key take-home messages for urologists based on these findings?

Darolutamide transformed the standard of care for patients with mHSPC as the first successful combination of a second-generation ARi with docetaxel. These results further demonstrate that the OS benefits conferred by this therapy are maintained throughout the disease course and are a valuable treatment option for those with this disease.

Is there anything else that you’d like to add?

Great strides are being made in prostate cancer care, but we know there remains a high need for new treatment options that delay disease progression, extend survival, and preserve quality of life. Prostate cancer requires urologists and oncologists to work together utilizing their unique skill sets to introduce early intervention of treatment, paving the way for shared, collaborative patient care. Not only is collaboration between physicians specializing in urology and oncology increasing, but it is also becoming more necessary across other therapeutic areas focused on improving patient care.

References

1. Shore ND, Tombal BF, Hussain MHA, et al. Overall survival with daroluatamide vs placebo in combination with androgen-deprivation therapy (ADT) and docetaxel: A sensitivity analysis from ARASENS accounting for subsequent therapy. Presented at the 2024 ASCO Genitourinary Cancers Symposium. San Francisco, California. January 25-27, 2024. Abstract 166.

2. Smith MR, Hussain MHA, Saad F, et al. Overall survival with darolutamide versus placebo in combination with androgen-deprivation therapy and docetaxel for metastatic hormone-sensitive prostate cancer in the phase 3 ARASENS trial. Presented at the 2022 ASCO Genitourinary Cancers Symposium. San Francisco, California. February 17-19, 2022. Abstract 13