Treatment Intensification in Metastatic Hormone Sensitive Prostate Cancer (mHSPC): Metachronous High Volume mHSPC

Since 2015, multiple combination treatment strategies have emerged for the management of patients with metastatic hormone sensitive prostate cancer (mHSPC). The addition of docetaxel and/or androgen receptor-axis targeted (ARAT) agents to standard androgen deprivation therapy (ADT), in the form of doublet and triplet treatment strategies, has demonstrated overall survival benefits in this cohort of patients. As such, these drug combinations have changed the standard of care approaches in these men.1

The incidence of metastatic prostate cancer at diagnosis ranges from ~5-50%, with significant geographic differences as previously described.2 Such patients are defined as having de novo or synchronous mHSPC. Additionally, there exits a subset of men initially diagnosed with non-metastatic disease, many of whom have received prior definitive local treatment, who will have progression to a metastatic state prior to development of castration resistance. This is known as metachronous mHSPC. This distinction between synchronous (i.e. de novo) and metachronous presentations is of utmost clinical importance given the known differences in underlying genomic mutational profiles and prognoses, influencing the subsequent choice of treatment intensification.3,4 These two cohorts can be further subdivided based on the volume of metastatic disease at presentation: low and high volumes. The CHAARTED high-volume criteria have been widely adopted in clinical practice, with high volume patients defined as follows: presence of visceral metastases or ≥4 bone lesions with ≥1 beyond the vertebral bodies and pelvis.5

As such four distinct subgroups become clinically relevant (median overall survival per CHAARTED and GETUG-15 among men receiving ADT alone, ie. the control groups in these trials):

  1. Synchronous and high volume: 3 years
  2. Synchronous and low volume: 4.5 year
  3. Metachronous and high volume: 4.5 years
  4. Metachronous and low volume: ~8 years
While early, aggressive treatment intensification with triplet regimens, with or without primary radiotherapy, may seem attractive in this cohort of patients to maximize survival outcomes, the reality is that such “maximal” treatment intensification likely represents overtreatment in a significant proportion of these patients. Furthermore, treatment toxicity, both from a pathophysiologic and financial standpoint, must be considered in these patients. As such, a nuanced approach to the treatment of such patients, guided by the aforementioned four presentations (synchronous high volume, synchronous low volume, metachronous high volume, metachronous low volume) is thus needed.

Index Patient 3: Metachronous High Volume mHSPC

Case Presentation: A 65-year-old previously healthy male with an ECOG performance status of 1 presents to his urologist to re-establish care for his prostate cancer. The patient had been previously diagnosed with prostate cancer Gleason Score 8 (4+4) in 4/16 cores five years prior and had received conventionally fractionated external beam radiotherapy with concurrent androgen deprivation therapy for 18 months. At the time of diagnosis, staging work up with conventional imaging (CT abdomen/pelvis and bone scan) were both negative, and his serum PSA had nadired from 7.90 ng/ml to 0.86 ng/ml. The patient was subsequently lost to follow-up as he had moved across the country and had lost his insurance coverage. At the time of re-presenting, the patient was found to have a PSA of 48.1 and was complaining of mid/lower back pain. A staging work up with a CT and bone scan demonstrated evidence of three lumbar (L2-L4) and a left femoral osteoblastic lesion. The remaining work up demonstrated evidence of anemia (Hgb: 10.1 g/dL), otherwise unremarkable.

Doublet Therapy: ARAT + ADT

When considering patients with mHSPC along a risk continuum, from good risk (metachronous low volume: 8-year median overall survival with ADT alone) to poor risk (synchronous high volume: 3-year median overall survival with ADT alone), patients with synchronous low volume and metachronous high volume (median overall survival: 4.5 years with ADT alone) mHSPC may both be considered as intermediate risk disease. As such, the clinical treatment approach for these two subgroups has significant overlap - ARATs + ADT have similarly served as the backbone for treatment of these patients. Patients with metachronous, high volume mHSPC have historically accounted for only a small proportion of patients in the published phase III trials, and as such, post-hoc analyses have been underpowered for evaluating this subgroup. Results from the ARCHES trial have demonstrated a 23% decreased hazard of overall mortality in this subgroup with addition of enzalutamide to ADT (HR: 0.77; 95% CI: 0.39 to 1.50).12

Doublet Therapy: Docetaxel + ADT

Results from the STOPCAP M1 collaborative meta-analysis of individual patient data from GETUG-15, STAMPEDE, and CHAARTED demonstrated that docetaxel addition to ADT in patients with metachronous, high volume prostate cancer is associated with significant improvements in overall survival (HR: 0.64, 95% CI: 0.42 to 0.99).


Triplet Therapy: Docetaxel + ARAT + ADT

Do these patients benefit from further treatment intensification with both docetaxel and an ARAT? Given that the PEACE-1 trial included patients with de novo mHSPC only, and ARASENS, to date, has no subgroup analyses by CHAARTED risk group criteria, the only available data to assess the benefit of triplet therapy in this mHSPC subgroup is from the ENZAMET updated analysis presented at ASCO 2022. As demonstrated in the Kaplan Meier analysis below, there does not appear to be a benefit to treatment intensification with both docetaxel and ARAT in this subgroup.


Given the relative increased toxicity with taxanes, along with a subset of patients being “chemotherapy unfit”, it appears that doublet therapy with an ARAT + ADT is the favored treatment approach in patients with metachronous high volume disease, with docetaxel reserved for select patients with higher volume of disease.

Written by:
  • Rashid K. Sayyid, MD, MSc, University of Toronto, Toronto, Ontario
  • Zachary Klaassen, MD, MSc, Medical College of Georgia, Augusta, Georgia, USA
Published: February 2023
Written by: Rashid K. Sayyid, MD MSc and Zachary Klaassen, MD,MSc
  1. Weiner AB, Siebert AL, Fenton SE, et al. First-line Systemic Treatment of Recurrent Prostate Cancer After Primary or Salvage Local Therapy: A Systematic Review of the Literature. Eur Urol Oncol. 2022.
  2. Cancer Stat Facts: Prostate Cancer. National Cancer Institute. Available at Accessed: Nov 14, 2022
  3. Deek MP, Van der Eecken K, Phillips R, et al. The mutational landscape of metastatic castration-sensitive prostate cancer: the spectrum theory revisited. Eur Urol. 2021;80:632-640
  4. Stopsack KH, Nandakumar S, Wimber AG, et al. Oncogenic genomic alterations, clinical phenotypes, and outcomes in metastatic castration-sensitive prostate cancer. Clin Cancer Res. 2020;26:3230-3238.
  5. Sweeney CJ, Chen Y, Carducci M, et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. N ENgl J Med. 2015;373:737-746.
  6. Fizai K, Foulon S, Carles J, 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. Lancet 2022;399(10336):1695-1707.
  7. Smith MR, Hussain M, Saad F, et al. Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer. N Engl J Med. 2022;386(12):1132-1142.
  8. Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. N Engl J Med. 2019;381(2):121-131.
  9. Hoyle AP, Ali A, James ND, et al. Abiraterone in “High-” and “Low-risk” Metastatic Hormone-sensitive Prostate Cancer. Eur Urol. 2018;76(6):719-728.
  10. James ND, de Bono JS, Spears MR, et al. Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. N Engl J Med. 2017;377:338-351.
  11. Chi KN, Chowdhury S, Bjartell A, et al. Apalutamide in Patients With Metastatic Castration-Sensitive Prostate Cancer: Final Survival Analysis of the Randomized, Double-Blind, Phase III TITAN Study. J Clin Oncol. 2021;39(2):2294-2303.
  12. Armstrong AJ, Szmulewitz RZ, Petrylak DP, 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(32):2974-2986.
  13. Parker CC, James ND, Brawley CD, et al. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. Lancet. 2018;392(10162):2353-2366.
  14. Boeve LMS, Hulshof MCCM, Vis AN, et al. Effect on Survival of Androgen Deprivation Therapy Alone Compared to Androgen Deprivation Therapy Combined with Concurrent Radiation Therapy to the Prostate in Patients with Primary Bone Metastatic Prostate Cancer in a Prospective Randomised Clinical Trial: Data from the HORRAD Trial. Eur Urol. 2019;75(3):410-418.
  15. Ost P, Reynders D, Decaestecker K, et al. Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence: A prospective, randomized, multicenter phase II trial. J Clin Oncol. 2018;36(5):446-453.
  16. Phillips R, Shi WY, Deek M, et al. Outcomes of Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer The ORIOLE Phase 2 Randomized Clinical Trial. JAMA Oncol. 2020;6(5):650-659.
  17. Deek MP, van der Eecken K, Sutera P, 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;JCO2200644.
  18. Palma DA, Olson R, Harrow S, et al. Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomised, phase 2, open-label trial. Lancet. 2019;393(10185):2051-2058.