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Androgen Deprivation Therapy Plus Chemotherapy ±  Androgen Receptor-Targeting Agents for Metastatic Hormone-sensitive Prostate Cancer - Beyond the Abstract

In the last decade, the treatment landscape for metastatic hormone-sensitive prostate cancer (mHSPC) has drastically changed due to the introduction of docetaxel and subsequently approval of novel hormone therapy (Androgen receptor-targeting agents [ARAT]) in combination with androgen deprivation therapy (ADT) resulting in prolonged overall survival rates.1-8

Following the results of PEACE-1 and ARASENS– both comparing triplet therapy consisting of ARAT [PEACE-1: abiraterone; ARASENS: darolutamide] + docetaxel + ADT to doublet therapy (docetaxel + ADT) - once again a new, fast evolving chapter for mHSPC treatment has started.9,10 As mHSPC patients represent a heterogenous cohort in terms of patient and tumor composition, identifying those mHSPC patients who specifically benefit from triplet therapy compared to doublet therapy is of utmost importance. In line with other publications, Wenzel et al. concluded in their review (Androgen deprivation therapy plus chemotherapy ± androgen receptor-targeting agents for metastatic hormone-sensitive prostate cancer) that the new backbone for mHSPC treatment should consist of either doublet therapy (ARAT + ADT) or triplet therapy (ARAT + docetaxel + ADT), indicating that doublet therapy (docetaxel + ADT) and ADT alone is outdated under the light of numerous network meta-analysis previously performed.11–13

Unfortunately, at that time, disease volume specific data (according to CHAARTED criteria) were only available for one triplet therapy regimen (PEACE-1). However, most recently Hussain et al. presented survival data stratified according to disease volume for the second triplet therapy regimen (ARASENS) at the 2023 ASCO Genitourinary Cancers Symposium.14 In line with the results of PEACE-1, in ARASENS especially the high-volume cohort demonstrated a statistically significant overall survival benefit (HR: 0.69; 95%CI: 0.57-0.82) of triplet therapy compared to doublet therapy (docetaxel + ADT).14

In the subgroup of low-volume mHSPC patients, up-to-date no significant benefit for the triplet therapy could be shown (HR: 0.68; 95%CI: 0.41-1.13). Still, one has to take into account, that data is immature and therefore results can change with a longer Follow-up.

It is of note that most recently, an updated network meta-analysis, incorporating PEACE-1 and most recent ARASENS data, with a focus on disease volume (low- vs high-volume) was performed.15 Here, a significant longer OS could be proven for the triplet therapy in high-volume, while in a low-volume setting no difference compared to ARAT + ADT was present. This data represents meaningful and highly-anticipated findings within the urological community.

Written by: Benedikt Hoeh, Mike Wenzel, Felix K.H. Chun & Philipp Mandel, Department of Urology, University Hospital Frankfurt, Goethe University Frankfurtam Main, Frankfurt am Main, Germany

References:

  1. Kyriakopoulos CE, Chen YH, Carducci MA, Liu G, Jarrard DF, Hahn NM, et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer: Long-Term Survival Analysis of the Randomized Phase III E3805 CHAARTED Trial. J Clin Oncol. 2018 Apr 10;36(11):1080–7.
  2. Clarke NW, Ali A, Ingleby FC, Hoyle A, Amos CL, Attard G, et al. Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer: long-term survival results from the STAMPEDE trial. Annals of Oncology. 2019 Dec;30(12):1992–2003.
  3. Chi et al. LATITUDE Study - Final Analysis of Phase III Study in Patients with Newly Diagnosed High-Risk Metastatic Castration-Naïve Prostate Cancer; 2019 American Society of Clinical Oncology Genitourinary Cancers Symposium, (ASCO GU) #GU19, February 14-16, 2019 - San Francisco, CA. 2019.
  4. Chi KN, Chowdhury S, Bjartell A, Chung BH, Pereira de Santana Gomes AJ, Given R, et al. Apalutamide in Patients With Metastatic Castration-Sensitive Prostate Cancer: Final Survival Analysis of the Randomized, Double-Blind, Phase III TITAN Study. JCO. 2021 Jul 10;39(20):2294–303.
  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 Jul 11;381(2):121–31.
  6. Armstrong et al. Final Overall Survival Analysis From ARCHES: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Enzalutamide + ADT in Men With mHSPC; 2021 European Society for Medical Oncology (ESMO) Annual Congress 2021, Thursday, Sep 16, 2021 – Tuesday, Sep 21, 2021. 2021.
  7. Hoyle AP, Ali A, James ND, Cook A, Parker CC, de Bono JS, et al. Abiraterone in “High-” and “Low-risk” Metastatic Hormone-sensitive Prostate Cancer. European Urology. 2019 Dec;76(6):719–28.
  8. Hoeh B, Würnschimmel C, Flammia RS, Horlemann B, Sorce G, Chierigo F, et al. Improvement in overall and cancer‐specific survival in contemporary, metastatic prostate cancer chemotherapy exposed patients. The Prostate. 2021 Sep 15;pros.24235.
  9. Fizazi K, Foulon S, Carles J, Roubaud G, McDermott R, Fléchon 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 × 2 factorial design. The Lancet. 2022 Apr;S0140673622003671.
  10. 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 Feb 17;NEJMoa2119115.
  11. Mandel P, Hoeh B, Wenzel M, Preisser F, Tian Z, Tilki D, et al. Triplet or Doublet Therapy in Metastatic Hormone-sensitive Prostate Cancer Patients: A Systematic Review and Network Meta-analysis. European Urology Focus. 2022 Sep;S2405456922001766.
  12. Yanagisawa T, Rajwa P, Thibault C, Gandaglia G, Mori K, Kawada T, et al. Androgen Receptor Signaling Inhibitors in Addition to Docetaxel with Androgen Deprivation Therapy for Metastatic Hormone-sensitive Prostate Cancer: A Systematic Review and Meta-analysis. European Urology. 2022 Dec;82(6):584–98.
  13. Roy S, Sayyid R, Saad F, Sun Y, Lajkosz K, Ong M, et al. Addition of Docetaxel to Androgen Receptor Axis–targeted Therapy and Androgen Deprivation Therapy in Metastatic Hormone-sensitive Prostate Cancer: A Network Meta-analysis. European Urology Oncology. 2022 Oct;5(5):494–502.
  14. 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. JCO. 2023 Feb 16;JCO.23.00041. 
  15. Hoeh B, Garcia CC, Wenzel M, Tian Z, Tilki D, Steuber T, et al. Triplet or Doublet Therapy in Metastatic Hormone-sensitive Prostate Cancer: Updated Network Meta-analysis Stratified by Disease Volume. European Urology Focus. 2023 Apr;S2405456923000949.
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