2. UroToday Home
  3. Recent Abstracts
  4. Urologic Oncology
  5. Prostate Cancer

The Efficacy of Enzalutamide plus Androgen Deprivation Therapy in Oligometastatic Hormone-sensitive Prostate Cancer: A Post Hoc Analysis of ARCHES - Beyond the Abstract

The past decade has seen a rapid expansion of systemic treatment options for metastatic hormone-sensitive prostate cancer (mHSPC), with multiple clinical trials showing significant improvements in overall survival (OS) with the addition of docetaxel,1,2 androgen receptor pathway inhibitors (ARPI),3-7 or docetaxel plus ARPI to androgen deprivation therapy (ADT).8,9 Nevertheless, real-world studies indicate that a majority of patients with mHSPC still receive ADT +/- first-generation nonsteroidal antiandrogens.10,11 Patients with oligometastatic disease, typically defined as 1-5 metastases, may be especially at risk of not receiving intensified systemic therapy given their more favorable prognosis.12 Although the use of metastasis-directed therapy (MDT) for oligometastatic HSPC has garnered much attention,13-15 this approach has not been yet proven to extend overall survival (OS).

To help define the optimal systemic treatment of oligometastatic HSPC, we conducted a post-hoc analysis for 927 patients with nonvisceral mHSPC in the ARCHES trial (NCT02677896). ARCHES is a randomised phase III clinical trial that showed enzalutamide added to ADT compared to placebo + ADT significantly improved all clinical outcomes including OS and radiographic progression-free survival (rPFS) in mHSPC.3,4 For the purpose of this analysis, HSPC was categorized as oligometastatic (1–5 metastases) or polymetastatic (6 metastases) based on conventional CT/MRI and bone scan imaging, with the treatment effect on rPFS, OS, and secondary endpoints assessed in terms of number of metastatic lesions.

Significant improvements in rPFS were seen favouring enzalutamide + ADT for patients with ≤5 metastases (HR 0.27, 95% CI 0.16–0.46; p < 0.001) and >6 metastases (HR 0.59, 95% CI 0.40–0.87; p < 0.005). Similarly, enzalutamide + ADT also significantly improved OS in patients with ≤5 metastases (HR 0.33, 95% CI 0.23–0.46; p < 0.001) and >6 metastases (HR 0.55, 95% CI 0.41–0.74; p < 0.001). Comparable results were seen for all other secondary endpoints including time to PSA progression, time to first symptomatic skeletal event, time to initiation of new antineoplastic therapy, PSA undetectable rate, and objective response rate. Notably, within the oligometastatic group, a consistent treatment effect was seen irrespective of the number of metastases, with the point estimates uniformly favouring enzalutamide including for patients with just 1 metastasis (rPFS: HR 0.27, 95% CI 0.06–1.30; OS: HR 0.58, 95% CI 0.22–1.52).

Our data provide level 1 evidence supporting the use of enzalutamide + ADT in all patients with mHSPC, irrespective of their metastatic burden. Importantly, this effect remained consistent in patients with as few as 1 non-visceral metastasis. Notably, the recent phase II EXTEND trial indicated a benefit to combining MDT with systemic therapy (ADT +/- ARPI) in oligometastatic HSPC(16). Although this supports further studies of MDT, at this point in time long-term continuous doublet systemic therapy with an ADT + ARPI remains the standard of care for oligometastatic HSPC. However, combining data from ARCHES and other phase III trials of doublet therapy and EXTEND and other randomized trials of PET directed RT such as STOMP suggests that cessation of systemic therapy after combined ADT/ARSI and MDT, either using PET or conventional imaging may in the future provide a nice balance between excellent disease control and improved qualify of life off therapy for those who obtain a complete remission. This deserves prospective controlled testing, such as in the ongoing STAMPEDE trial.

Written by: Andrew J. Armstrong, MD ScM FACP, Duke University, Durham NC & Arun Azad, MD, Peter MacCallum Cancer Centre, Melbourne, Australia

References:

  1. Sweeney CJ, Chen YH, Carducci M, Liu G, Jarrard DF, Eisenberger M, et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. N Engl J Med. 2015;373:737-46.
  2. James ND, Sydes MR, Clarke NW, Mason MD, Dearnaley DP, Spears MR, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2016;387:1163-77.
  3. Armstrong AJ, Azad AA, Iguchi T, Szmulewitz RZ, Petrylak DP, Holzbeierlein J, et al. Improved Survival With Enzalutamide in Patients With Metastatic Hormone-Sensitive Prostate Cancer. J Clin Oncol. 2022;40:1616-22.
  4. Armstrong AJ, Szmulewitz RZ, Petrylak DP, Holzbeierlein J, Villers A, Azad A, et al. ARCHES: A Randomized, Phase III Study of Androgen Deprivation Therapy With Enzalutamide or Placebo in Men With Metastatic Hormone-Sensitive Prostate Cancer. J Clin Oncol. 2019;37:2974-86.
  5. Davis ID, Martin AJ, Stockler MR, Begbie S, Chi KN, Chowdhury S, et al. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. N Engl J Med. 2019;381:121-31.
  6. Fizazi K, Tran N, Fein L, Matsubara N, Rodriguez-Antolin A, Alekseev BY, et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med. 2017;377:352-60.
  7. Chi KN, Agarwal N, Bjartell A, Chung BH, Pereira de Santana Gomes AJ, Given R, et al. Apalutamide for Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med. 2019;381:13-24.
  8. 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;386:1132-42.
  9. 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;399:1695-707.
  10. Swami U, Sinnott JA, Haaland B, Sayegh N, McFarland TR, Tripathi N, et al. Treatment Pattern and Outcomes with Systemic Therapy in Men with Metastatic Prostate Cancer in the Real-World Patients in the United States. Cancers (Basel). 2021;13.
  11. Swami U, Hong A, El-Chaar NN, Ramaswamy K, Diessner BJ, Blauer-Peterson CJ, et al. The Role of Physician Specialty in the Underutilization of Standard-of-Care Treatment Intensification in Patients With Metastatic Castration-sensitive Prostate Cancer. J Urol. 2023;209:1120-31.
  12. Lievens Y, Guckenberger M, Gomez D, Hoyer M, Iyengar P, Kindts I, et al. Defining oligometastatic disease from a radiation oncology perspective: An ESTRO-ASTRO consensus document. Radiother Oncol. 2020;148:157-66.
  13. Phillips R, Shi WY, Deek M, Radwan N, Lim SJ, Antonarakis ES, et al. Outcomes of Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer: The ORIOLE Phase 2 Randomized Clinical Trial. JAMA Oncol. 2020;6:650-9.
  14. Deek MP, Van der Eecken K, Sutera P, Deek RA, Fonteyne V, Mendes AA, et al. Long-Term Outcomes and Genetic Predictors of Response to Metastasis-Directed Therapy Versus Observation in Oligometastatic Prostate Cancer: Analysis of STOMP and ORIOLE Trials. J Clin Oncol. 2022;40:3377-82.
  15. Siva S, Bressel M, Murphy DG, Shaw M, Chander S, Violet J, et al. Stereotactic Abative Body Radiotherapy (SABR) for Oligometastatic Prostate Cancer: A Prospective Clinical Trial. Eur Urol. 2018;74:455-62.
  16. Tang C, Sherry AD, Haymaker C, Bathala T, Liu S, Fellman B, et al. Addition of Metastasis-Directed Therapy to Intermittent Hormone Therapy for Oligometastatic Prostate Cancer: The EXTEND Phase 2 Randomized Clinical Trial. JAMA Oncol. 2023.
Read the Abstract