Treatment Intensification in Metastatic Hormone Sensitive Prostate Cancer (mHSPC) Cases - Synchronous 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.

In this Center of Excellence review article, we present Index Patient 1: Synchronous High Volume mHSPC

Index Patient 1: Synchronous High Volume mHSPC

Case Presentation: A 57-year-old previously healthy male with an excellent performance status presents to his primary care physician with complaints of intermittent right hip pain for the last three months. Screening blood work in the form of a complete blood count (CBC) and a comprehensive metabolic panel (CMP) demonstrates elevated liver function tests. A computed tomography scan of the abdomen and pelvis (CT A/P) demonstrates evidence of two bony lesions in the right femur and iliac bone, multiple liver lesions, pelvic nodal enlargement bilaterally, and an enlarged, heterogenous prostate gland. A serum prostate-specific antigen (PSA) test was drawn and demonstrated to be 306.2 ng/ml. A bone scan was obtained and demonstrated no additional lesions. A subsequent CT chest demonstrated small, non-specific lesions in the lower lobes bilaterally. Gleason Score 9 (4+5) prostate cancer was diagnosed in 9/12 cores, confirming synchronous, high volume mHSPC disease.

Triplet Therapy

Based on the results from PEACE-1 and ARASENS, as well as subgroup analysis from ENZAMET, it appears that this patient cohort, particularly those who are chemotherapy-fit such as this patient, are most likely to benefit from triplet therapy with docetaxel + an ARAT + ADT.

ADT + Docetaxel + Abiraterone

Initially presented at ASCO 2021 and subsequently published in the Lancet in 2022,22 the PEACE-1 trial employed a 2x2 design to assess, (separately and combined) the impact of the addition of abiraterone + prednisone +/- radiation therapy to standard of care therapy in men with de novo mHSPC. Among patients with high volume disease, the addition of abiraterone + prednisone to standard of care resulted in a 53% improvement in radiographic progression-free survival (rPFS) with median rPFS of 1.6 years on the standard of care arm and 4.1 years on the standard of care plus abiraterone + prednisone arm (HR: 0.47, 95% CI: 0.36 to 0.60). The addition of abiraterone + prednisone to standard of care in patients with low volume disease still resulted in a 42% improvement in rPFS with median rPFS of 2.7 years on the standard of care arm versus not yet reached on the standard of care plus abiraterone + prednisone + ADT arm (HR 0.58, 95% CI 0.39-0.87). With regards to overall survival in patients with a de novo presentation, a benefit was seen mainly in those with high-volume disease (median overall survival 5.14 versus 3.57 years; HR 0.77, 95% CI 0.62 to 0.96), with a marginal, non-significant improvement in those low volume de novo disease (median overall survival not reached; HR 0.93, 95% CI 0.69 to 1.28). The OS data is immature for the low volume patients due to a small number of events.

Notably, 81% of patients in the ADT plus docetaxel standard of care control arm subsequently received a next generation hormonal therapy at the time of disease progression. This suggests that early intensification with the addition of abiraterone + prednisone to standard of care therapy results in improvement in rPFS and OS compared to sequential therapy:6


ADT + Docetaxel + Darolutamide

The ARASENS trial evaluating addition of darolutamide to standard of care therapy consisting of ADT + docetaxel was presented at ASCO GU 2022 and concurrently published in The New England Journal of Medicine. Metastatic burden classification by CHAARTED criteria was not available in this trial, however, disease stratification by TNM metastatic burden (M1b versus M1c) demonstrated consistent benefits for darolutamide addition to ADT and docetaxel. In the M1b subgroup (with bone metastases), HR for overall survival was 0.66 (95% CI: 0.54 to 0.80). In the M1c group (with visceral metastases), HR for OS was 0.76 (95% CI: 0.53 to 1.10), with median OS of 49.0 months in the darolutamide arm and 42.0 months in the placebo arm:


When stratified by alkaline phosphatase levels, consistent overall survival benefits were seen both in patients with an alkaline phosphatase level above or equal to the upper limit of normal (median overall survival: 49.0 versus 42.0 months; HR: 0.76, 95% CI: 0.56 to 0.85) and a level below the upper limit of normal (median overall survival: 69.0 versus 60.6 months; HR: 0.64, 95% CI: 0.52 to 0.79):7


ADT + Enzalutamide vs ADT

While the ENZAMET trial was designed to compare the combination of ADT + enzalutamide versus ADT + standard nonsteroidal antiandrogen, the study design allowed for previous/concurrent use of docetaxel. In this trial, six cycles of docetaxel were given to 65% of patients in the enzalutamide group versus 76% in the standard of care group. As such, it may be argued that results from this study served as the first indication for the benefits of triplet therapy in this disease space.8 An overall survival benefit for enzalutamide addition (versus a nonsteroidal anti-androgen) was seen irrespective of planned early docetaxel use, volume of disease, or timing of presentation:

  • Planned early docetaxel (p-value for interaction = 0.09)
    • Yes: HR 0.82 (95% CI 0.63 to 1.06)
    • No: HR 0.60 (95% CI 0.47 to 0.78)
  • Volume of disease (p-value for interaction = 0.06)
    • Low: HR 0.54 (95% CI 0.39 to 0.74)
    • High: HR 0.79 (95% CI 0.63 to 0.98)
  • Timing of presentation (p-value for interaction = 0.91)
    • Synchronous: HR 0.70 (95% CI 0.56 to 0.87)
    • Metachronous: HR 0.71 (95% CI 0.52 to 0.98)
Updated results were presented at ASCO 2022, with survival outcomes stratified by disease volume (high versus low) and presentation (synchronous versus metachronous). Based on these subgroup analyses, it appears that those with synchronous, high-volume mHSPC were the only ones to benefit from early treatment intensification, with the Kaplan Meier curves below demonstrating early separation of the enzalutamide/docetaxel arm from the remaining ones (enzalutamide, NSAA, NSAA + docetaxel):


Results from these three trials provide strong evidence to support the use of a triple regimen approach in patients with synchronous, high volume mHSPC. It bears note, however, that routine use of docetaxel may not be feasible in patients with contraindications to taxane therapy, including poor performance status, blood dyscrasias, and peripheral neuropathy. Such patients would likely benefit from ARAT addition to standard ADT:


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.