The Efficacy of Darolutamide for Non Metastatic Castration-Resistant Prostate Patients

In July 2019, darolutamide became the newest available oral androgen receptor inhibitor approved by the FDA for the treatment of nonmetastatic castration-resistant prostate cancer (nmCRPC) patients. The Phase 3 ARAMIS trial evaluated darolutamide with androgen deprivation therapy (ADT) versus ADT plus placebo for nmCRPC patients and demonstrated significant improvement in metastasis-free survival (MFS), extending MFS to 40 months for those treated with darolutamide as opposed to 18 months for patients randomized to the ADT + placebo arm.

 

Novel approaches for the treatment of nmCRPC are now NCCN recommended, as the preferred approach to thwart prostate cancer progression for nmCRPC patients. With the awareness of a rising PSA with castrate levels of testosterone, and a lack of metastases with CT and Bone scan imaging, novel oral AR inhibitors will improve MFS., thus the importance of routine and appropriate PSA monitoring with attendant radiographic imaging. Darolutamide’s approval, licensed with the commercial name, Nubeqa, provides the arrival of another important therapeutic option for extending MFS in nmCRPC patients.

The Phase 3 ARAMIS trial was a global randomized trial consisting of 1509 nmCRPC patients; its positive results led to the inclusion of darolutamide in the standard of care repertoire for the treatment of nmCRPC. At ASCO GU 2019, Karim Fizazi, MD, Ph.D., sat down with Alicia Morgans, MD, MPH to discuss the results of ARAMIS. They discussed how the use of darolutamide showed a robust safety profile, few drug-drug interactions, and a paucity of serious adverse event side effects. The trial results and darolutamide’s FDA approval have initiated numerous additional advanced prostate cancer trials.

An insightful conversation on ARAMIS from ASCO GU 2019 was an interview between Petros Grivas, MD, Ph.D. and Neeraj Agarwal, MD. Agarwal commented on the practice-changing nature of the study and Karim Fizazi’s presentation of ARAMIS at ASCO GU 2019. Agarwal comments that the result of an almost 22-month extension of MFS is impressive. He notes that the drugs unique mode of action with the benefit of minimal penetration across the blood brain barrier has very positive avoidance of central nervous system side effects, which has been reported with other approved nmCRPC therapies.

The recent success of Darolutamide builds off of landmark trials such as SPARTAN and PROSPER which investigated the efficacy of apalutamide and enzalutamide respectively for patients with nmCRPC. Comparing the three trials, one can ascertain differences in efficacy endpoints, mild inclusion criteria differences, and common adverse events reported. Direct comparator trials have not yet been reported. Of note, darolutamide has a unique molecular structure as an oral androgen receptor inhibitor. In conclusion, the positive results of the three nmCRPC trials have clearly augmented the treatment armamentarium for the benefit of nmCRPC patients.

Looking forward to the new year, the recent advancements in the nmCRPC disease space, as well as metastatic castration sensitive prostate cancer (mCSPC), should inspire ongoing and additional trials to amplify benefits for advanced prostate cancer patients. As ARAMIS was an important part of the nmCRPC narrative in 2019, its promising efficacy and tolerability will hopefully present physicians, researchers, and patients with additional therapeutic approaches within the prostate cancer continuum.

Written by: Neal Shore, MD, FACS, Medical Director of the Carolina Urologic Research Center, Atlantic Urology Clinics, Myrtle Beach, South Carolina

Published Date: January 20th, 2020

Further Related Content:
Read: Darolutamide: Approved For Non-Metastatic Castration-Resistant Prostate Cancer
Read: ARAMIS: Efficacy and Safety of Darolutamide in nmCRPC | ASCO GU 2019
Watch: ARAMIS Trial in Prostate Cancer: Impact of Darolutamide on Pain and Quality of Life - Karim Fizazi

Physician-Scientist Review Articles
State of the Evidence Review Articles
Written by Christopher J.D. Wallis, MD, PhD and Zachary Klaassen, MD, MSc
September 17, 2020
While there have been dramatic changes in treatment options for patients with advanced prostate cancer over the past 5 years, perhaps the greatest change has been for patients with non-metastatic castration-resistant prostate cancer (nmCRPC). Prior to February 14, 2018, there were no agents approved by the United States Food and Drug Administration (FDA) for men with nmCRPC.
Written by Jeanny B. Aragon-Ching, M.D., F.A.C.P.
May 15, 2020
Darolutamide is a novel anti-androgen that is recently approved for men with non-metastatic castration-resistant prostate cancer. Darolutamide is structurally different from the previously discovered androgen receptor (AR) agents enzalutamide, bicalutamide and apalutamide. Early phase trials showed promising results with overall safety profiles that are generally well-tolerated.
Written by Zachary Klaassen, MD, MSc and Christopher J.D. Wallis, MD, PhD
April 16, 2019
Over the last two or more years, the treatment of men with M0 CRPC has drastically changed, most recently with the approval of darolutamide in this disease space based on data from the ARAMIS trial. The objective of this article is to provide a contemporary review of treatment options for men with non-metastatic CRPC.
Conference Coverage
Conference Highlights Written by Physician-Scientist
Presented by Evan Yu, MD

At the 2022 ASCO Annual Meeting, the poster session focused on Prostate, Testicular, and Penile cancers included a presentation from Dr. Evan Yu examining real-world outcomes for patients treated with darolutamide in advanced prostate cancer.

 

Presented by Amanda E. Hird, MD,
 In a moderated poster presentation at the 2022 American Urologic Association Annual Meeting held in New Orleans and virtually, Dr. Hird presented results of a population-based analysis of the prevalence and natural history of non-metastatic castration-resistant prostate cancer (nmCRPC).
Presented by Karim Fizazi, MD, PhD
Darolutamide (DARO) is a structurally distinct androgen receptor inhibitor (ARI) that has been demonstrated to significantly prolong metastasis-free survival and overall survival in the ARAMIS trial.1
Presented by Susan Feyerabend
Darolutamide significantly prolonged metastasis-free survival (MFS) and overall survival (OS) vs placebo (PBO) in men with nonmetastatic castration-resistant prostate cancer (nmCRPC) in ARAMIS.
Presented by Karim Fizazi, MD, PhD
Patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) need therapy that prolongs survival with little added toxicity, thus preserving quality of life.
Presented by Neal D. Shore, MD, FAC
In plenary abstract presentation in the Poster Highlights Session: Prostate Cancer - Localized Disease session at the 2021 ASCO GU meeting, Dr. Shore and colleagues presented an analysis examining the effect of crossover on the overall survival benefit seen in ARAMIS.
Presented by Maha H. A. Hussain, MD, FACP, FASCO
To provide guidance on expected outcomes and explore the influence of PSA dynamics further, in a plenary abstract presentation in the Poster Highlights Session: Prostate Cancer session at the 2021 ASCO GU Cancers Symposium, Dr. Hussain and colleagues presented an analysis of overall survival and metastasis-free survival among patients in the PROSPER trial according to the depth of PSA response.
Presented by Matthew R. Smith, MD, Ph.D
There has been a rapid evolution in treatment options for patients with non-metastatic castration-resistant prostate cancer (nmCRPC) since the spring of 2018. Up until the presentation of SPARTAN and PROSPER trials, reporting on the use of apalutamide and enzalutamide in nmCRPC
Presented by Alicia Morgans, MD, MPH 
In a stand-alone session at this year’s Society of Urologic Oncology (SUO) virtual annual meeting, titled Understanding the Evolving Treatment Landscape in Prostate Cancer: How to Leverage the Latest Advances and Strategies to Optimize Patient Outcomes,
Presented by Karim Fizazi, MD, Ph.D.
There has been a rapid evolution in treatment options for patients with non-metastatic castration-resistant prostate cancer (nmCRPC) since the spring of 2018. Up until the presentation of SPARTAN and PROSPER trials, reporting on the use of apalutamide and enzalutamide in non-metastatic castration-resistant prostate cancer, at GU ASCO in February 2018, there were no specifically approved treatment options for these patients.
Presented by Karim Fizazi, MD, PhD
There has been a rapid evolution in treatment options for patients with non-metastatic castration-resistant prostate cancer since the spring of 2018. Up until the presentation of SPARTAN and PROSPER trials, reporting on the use of apalutamide and enzalutamide in non-metastatic castration-resistant prostate cancer, at GU ASCO in February 2018, there were no specifically approved treatment options for these patients.
Presented by Karim Fizazi, MD, Ph.D.
Darolutamide is a unique androgen receptor inhibitor, FDA approved in July 2019 for the treatment of non-metastatic castration-resistant prostate cancer. This approval was based on ARAMIS,1 a large multicenter double-blind, placebo-controlled study that randomized 1500 patients to 600 milligrams of darolutamide twice a day or placebo.
Presented by Boris Hadaschik, MD
Athens, Greece (UroToday.com) Dr. Boris Hadaschik presented on the disease entity of non-metastatic castrate-resistant prostate cancer (nmCRPC).
Presented by Matthew R. Smith, MD, PhD
Barcelona, Spain (UroToday.com) The randomized, phase 3 SPARTAN trial showed that apalutamide offered a metastasis-free survival (MFS) benefit over placebo for patients with non-metastatic
Presented by Christopher Parker, MD
Barcelona, Spain (UroToday.com) The optimal timing of radiotherapy after radical prostatectomy for prostate cancer is uncertain. Supporters of adjuvant radiotherapy suggest that earlier treatment may be more effective,
Presented by Matthew R. Smith, MD, PhD
Barcelona, Spain (UroToday.com) In the phase III placebo-controlled SPARTAN study, apalutamide with ongoing androgen deprivation therapy (ADT) significantly improved metastasis-free survival (MFS) (HR 0.28, 95% CI, 0.23-0.35),
Presented by Teuvo Tammela, MD, PhD
Barcelona, Spain (UroToday.com)  Dr. Teuvo Tammela presented results of the recently published ARAMIS trial. Non-metastatic (M0) CRPC (nmCRPC) is defined as a rising PSA in the setting of non-metastatic disease in the castrate state.
Presented by Karim Fizazi, MD, PhD
San Francisco, CA (UroToday.com) The use of androgen-axis targeted agents, specifically enzalutamide and abiraterone, have drastically changed the landscape of advanced prostate cancer management. Just last year, at GU ASCO 2018,
Presented by Neil Fleshner, MD, MPH, FRCSC
Toronto, Ontario (UroToday.com) Dr. Neil Fleshner presented the question in debate of whether we should be treating non-metastatic castrate-resistant prostate cancer (nmCRPC) patients or wait until they have developed metastases.
Presented by Maha Hussain, MD, FACP, FASCO
San Francisco, CA (UroToday.com) Dr. Maha Hussain provided the first presentation of the phase III randomized double-blind controlled trial, the following men were eligible for inclusion
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