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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

  • Maha Hussain,
  • Bertrand Tombal,
  • Fred Saad,
  • Karim Fizazi,
  • Cora N. Sternberg,
  • E. David Crawford,
  • Neal Shore,
  • Evgeny Kopyltsov,
  • Arash Rezazadeh Kalebasty,
  • Martin Bögemann,
  • Dingwei Ye,
  • Felipe Cruz,
  • Hiroyoshi Suzuki,
  • Shivani Kapur,
  • Shankar Srinivasan,
  • Frank Verholen,
  • Iris Kuss,
  • Heikki Joensuu,
  • Matthew R. Smith

Publication: Journal of Clinical Oncology, February 2023


For patients with metastatic hormone-sensitive prostate cancer, metastatic burden affects outcome. We examined efficacy and safety from the ARASENS trial for subgroups by disease volume and risk.


Patients with metastatic hormone-sensitive prostate cancer were randomly assigned to darolutamide or placebo plus androgen-deprivation therapy and docetaxel. High-volume disease was defined as visceral metastases and/or ≥ 4 bone metastases with ≥ 1 beyond the vertebral column/pelvis. High-risk disease was defined as ≥ 2 risk factors: Gleason score ≥ 8, ≥ 3 bone lesions, and presence of measurable visceral metastases.


Of 1,305 patients, 1,005 (77%) had high-volume disease and 912 (70%) had high-risk disease. Darolutamide increased overall survival (OS) versus placebo in patients with high-volume (hazard ratio [HR], 0.69; 95% CI, 0.57 to 0.82), high-risk (HR, 0.71; 95% CI, 0.58 to 0.86), and low-risk disease (HR, 0.62; 95% CI, 0.42 to 0.90), and in the smaller low-volume subgroup, the results were also suggestive of survival benefit (HR, 0.68; 95% CI, 0.41 to 1.13). Darolutamide improved clinically relevant secondary end points of time to castration-resistant prostate cancer and subsequent systemic antineoplastic therapy versus placebo in all disease volume and risk subgroups. Adverse events (AEs) were similar between treatment groups across subgroups. Grade 3 or 4 AEs occurred in 64.9% of darolutamide patients versus 64.2% of placebo patients in the high-volume subgroup and 70.1% versus 61.1% in the low-volume subgroup. Among the most common AEs, many were known toxicities related to docetaxel.


In patients with high-volume and high-risk/low-risk metastatic hormone-sensitive prostate cancer, treatment intensification with darolutamide, androgen-deprivation therapy, and docetaxel increased OS with a similar AE profile in the subgroups, consistent with the overall population.

Prof. Igor Tsaur

Systemic treatment of metastatic hormone-sensitive prostate cancer (mHSPC) is constantly evolving. In recent years, upfront combination of the previous therapeutic cornerstone in this disease stage, androgen deprivation therapy (ADT), with novel hormonal agents (NHA) or docetaxel has changed the modern-day standard care. This drives the concept of ADT monotherapy literally to the outskirts of systemic care. However, optimal management of mHSPC, being prognostically tailored either depending on the presence of metastases at presentation or disease volume/risk is yet to be elucidated.

Recently, promising outcomes of a further intensification of systemic treatment combining ADT+NHA+docetaxel, the so-called triple therapy (TT), have been reported from PEACE-1 (NHA: abiraterone acetate) and ARASENS (NHA: darolutamide) trials (1, 2). Since neither the data from LATITUDE nor the final analysis of CHAARTED were available at the time of the conception of both studies on TT, subgroups based on disease volume and risk classification have not been prespecified. Nonetheless, assessment of treatment effect in these categories would be critical for further incorporation of triplet therapy in the clinical routine.

A post hoc assessment of ARASENS presented by Hussain and collaborators included 1305 males with mHSPC of which 77% had high-volume and 70% had high-risk disease (3). Longer duration of treatment was observed in men receiving darolutamide versus placebo in both high-/low-volume and high-/low-risk stratifications. A significant benefit in terms of overall survival (OS; primary end point) for TT over darolutamide+ADT was demonstrated for high-volume, high-risk and low-risk disease (HR: 0.69, 0.71, 0.62, respectively).

In low-volume mHSPC, the findings were suggestive of a survival advantage for TT with a HR of 0.68 but CIs crossing 1.0. This was further corroborated by an interaction test yielding a homogenous treatment effect across high- and low-volume subgroups. Time to castration resistance, time to subsequent antineoplastic therapy as well as survival free from symptomatic skeletal events (secondary efficacy end points) were all significantly prolonged by TT as compared to darolutamide+ADT independently of subgroup distribution.

Incidence of any as well as of serious adverse events (AEs) was comparable in patients treated by TT or darolutamide+ADT across all disease volume- and risk-based subgroups. Safety of darolutamide was further supported by favourable exposure-adjusted incidence rates for most common AEs (≥ 25% of patients) accounting for a longer treatment duration with TT.

An interesting finding from this post-hoc assessment is that, in addition to high-volume, high-risk and low-risk disease, TT might be beneficial over docetaxel+ADT even for patients with low-volume disease provided that suggested OS advantage will mature with a longer follow-up. However, since only 300 patients were classified as having low-volume mHSPC, the question arises if statistical significance may ever be reached in this subgroup. Furthermore, favourable safety profile of darolutamide in all analysed subgroups as well as absent drug interaction with docetaxel makes this compound a promising combination partner for treatment escalation.

Taking into account the current assumption that NHA+ADT is more efficacious than docetaxel+ADT for OS extension, the most crucial question that has yet to be clarified is whether TT would be beneficial over NHA+ADT instead of docetaxel+ADT. Since neutropenia as the far most common grade 3 or 4 AE in ARASENS is clearly docetaxel-driven (2), demonstration of comparable efficacy of TT and NHA+ADT across disease volume and risk subgroups would corroborate the value of the latter as the current standard of care.


  1. Fizazi K, Foulon S, Carles J, Roubaud G, McDermott R, Flechon A, et al. Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 x 2 factorial design. Lancet. 2022;399(10336):1695-707.
  2. Smith MR, Hussain M, Saad F, Fizazi K, Sternberg CN, Crawford ED, et al. Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer. N Engl J Med. 2022;386(12):1132-42.
  3. Hussain M, Tombal B, Saad F, Fizazi K, Sternberg CN, Crawford ED, 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. 2023:JCO2300041.