Over the past decade, the gold-standard treatment for metastatic hormone-sensitive prostate cancer (mHSPC) has evolved from single-agent androgen deprivation therapy (ADT) to the addition of a second agent (docetaxel), and possibly a third agent in the form of an androgen receptor inhibitor. Until recently, however, the findings from trials with triple therapy were inconsistent. Now, the results of the ARASENS trial, presented at the 2022 ASCO GU Cancers Symposium1 and published simultaneously in The New England Journal of Medicine,2 appear to have confirmed triple therapy as the new standard of care for mHSPC. In the trial, addition of the androgen receptor inhibitor darolutamide to ADT and docetaxel was associated with a significant overall survival benefit in patients with mHSPC compared with ADT plus docetaxel, with no increase in toxicity. Darolutamide is already approved worldwide for the treatment of patients with non-metastatic castration-resistant prostate cancer (nmCRPC), and the manufacturer of darolutamide, Bayer, has submitted applications in the US and Europe for the additional indication of treatment of mHSPC, based on the ARASENS data.3
In a Uromigos podcast conversation with Thomas Powles, MBBS, MD, (Barts Cancer Centre, London, UK) and Brian Rini, MD (Vanderbilt University, Nashville, TN), ASCO presenter and lead author of ARASENS, Matthew R. Smith, MD, PhD, Director of the Genitourinary Malignancies Program, Massachusetts General Hospital Cancer Center and Associate Professor of Medicine at Harvard Medical School, reviewed the results of the trial and their implications.
Dr Smith explained that ARASENS was designed in 2016, around the time when the first evidence that the addition of docetaxel to ADT improved overall survival in patients with mHSPC, so it seemed appropriate to design a trial comparing the doublet to the triplet. Patients with mHSPC and ECOG performance status 0-1 who were candidates for ADT and docetaxel, were enrolled in the trial between November 2016 and June 2018. A total of 1306 patients were randomized 1:1 to darolutamide or placebo within 12 weeks of starting standard ADT. Then patients in both groups were treated with docetaxel for 6 cycles, starting within 6 weeks of randomization, so darolutamide and docetaxel were administered concurrently.
Dr Powles noted similarities between the design of ARASENS and PEACE-1, a Phase 3 trial with a 2×2 factorial design in which abiraterone acetate added to ADT plus docetaxel in patients with mHSPC resulted in improvements in both radiographic progression-free survival rPFS and overall survival.4 However, PEACE-1 had a couple of complicating factors, he noted: these were amendments due to the evolving landscape and a randomization with local radiation therapy. ARASENS was designed entirely to address the question of whether triplet therapy, in this case addition of darolutamide, improves survival on top of ADT and docetaxel, he noted. “At the time ARASENS was designed, the standard of care was more or less fixed at ADT plus docetaxel, so we chose that as the control arm and avoided the complexities of PEACE-1 and ENZAMET and other trials of triple therapy where docetaxel was administered solely at the discretion of the treating physicians.” Dr Smith explained.
Patients in ARASENS were well balanced between the two treatment groups, with no notable differences between the groups in baseline demographics or disease characteristics “It is a joy as an investigator to report these kinds of data,” Dr Smith remarked. There was no interim analysis, only one final primary analysis for overall survival (October 25, 2021), prespecified and event-driven, which occurred after a total of 533 deaths. Compared with placebo, the risk of death was significantly lower by 32.5% with darolutamide (hazard ratio 0.68; 95% confidence interval, 0.57 to 0.80; P<0.0001). There was clear early and consistent separation between the darolutamide and placebo groups, Dr Smith noted. The treatment effect of darolutamide on overall survival was consistent across all prespecified subgroups, including stratification factors of extent of disease and baseline alkaline phosphatase level, as well as age, race, geographical region, baseline PSA and ECOG, Gleason score, and metastatic stage at initial diagnosis.
Key secondary endpoints were consistently benefited with darolutamide compared with placebo, including significantly longer time to CRPC (hazard ratio 0.36; 95% confidence interval, 0.30 to 0.42; P<0.001) and time to pain progression (hazard ratio 0.68; 95% confidence interval, 0.7 to 0.95; P<0.01). Darolutamide also significantly improved time to first symptomatic skeletal event and time to initiation of subsequent systemic antineoplastic therapy, he noted. Dr Smith stressed that the overall survival benefit seen with darolutamide occurred despite a high rate of subsequent therapy in the placebo group. “By the time of data cutoff, more than 75% of patients in the placebo group had received one or more subsequent life-prolonging therapies,” he pointed out. He believes that this observation improves the generalizability of the results and confirms that early use of darolutamide was responsible for improving overall survival.
Dr Smith noted that the favorable safety profile revealed with darolutamide in prior clinical experience in other disease settings was also seen in ARASENS, which showed similar rates of treatment-emergent adverse events, serious adverse events, and adverse events leading to permanent discontinuation of study treatments in the two groups. “As you might expect, Grade 3/4 adverse events such as neutropenia, febrile neutropenia and anemia were largely attributable to docetaxel treatment. but they were not increased with the addition of darolutamide,” Dr Smith added.
Dr Powles pointed to the difference between the ARASENS results and those of the ENZAMET trial, in which a subgroup analysis showed that addition of enzalutamide to ADT and docetaxel did not improve survival.5 Dr Smith admitted that the early observations from ENZAMET “created a lot of anxiety” as the investigators were waiting for the results of ARASENS. He proposed several potential explanations for the different findings. “One is that ENZAMET simply wasn’t designed to address that question, particularly since the decision to start early treatment with docetaxel was left up to the patients and the investigators,” he suggested. Also, docetaxel was given concurrently instead of sequentially. “Any one or combination of those factors could explain the different result of ENZAMET.”
Replying to Dr Rini’s question as to whether ARASENS has really established a new standard of care, Dr Smith replied that the ARASENS data and their consistency with the observations from PEACE-1 “nail down triple therapy as an appropriate and the preferred standard of care for many patients with mHSPC.” Both PEACE-1 and ARASENS included mostly patients with de novo metastatic disease and the vast majority of patients in both studies had bone metastases, so it is not possible to say that this triple therapy is the standard of care for all patients with mHSPC, Dr Smith commented. “Older, frailer patients may not be good candidates for docetaxel, and in patients with more favorable disease, either ADT alone or doublet therapy with an AR pathway inhibitor may be preferable,” he advised.
Dr Rini wanted to know how a practitioner should decide between abiraterone, used in PEACE-1, and darolutamide, used in ARASENS, for a patient with mHSPC. “I don’t think there is a large difference,” Dr Smith said. “With regard to doublet therapy, I would say that any AR pathway inhibitor would be fine.” However, triplet therapy raises the issue of safety and potential drug-drug interactions between any individual AR pathway inhibitor and docetaxel, he cautioned. “So at present, I would be comfortable recommending triple therapy including docetaxel and either abiraterone or darolutamide, but not other drugs, because I don’t think we have sufficient safety information about concurrent treatment,” he advised.
Linda Brookes, MSc is a freelance medical writer/editor based in New York and London.
- 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. J Clin Oncol. 2022;40(6 suppl):Abstract 13. DOI: 1200/JCO.2022.40.6_suppl.013
- Smith MR, Hussain M, Saad F, et al; ARASENSTrial Investigators. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. N Engl J Med. 2022;386(12):1132-1142. DOI: 1056/NEJMoa2119115
- Bayer submits applications in the U.S. and EU for additional indication of NUBEQA® (darolutamide). Bayer; March 9, 2022. Accessed March 14. https://www.businesswire.com/news/home/20220308006237/en/
- Fizazi K, Carles Galceran J, Foulon S, et al. A phase III trial with a 2×2 factorial design in men with de novo metastatic castration-sensitive prostate cancer: Overall survival with abiraterone acetate plus prednisone in PEACE-1. Ann Oncol. 2021;32(Suppl 5):S1299. DOI: https://doi.org/10.1016/j.annonc.2021.08.2099
- Davis ID, Martin AJ, Stockler MR, et al; ENZAMET Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019;381(2):121-131. DOI: 10.1056/NEJMoa1903835