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Treatment Intensification in Metastatic Hormone Sensitive Prostate Cancer (mHSPC): Metachronous Low 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 exists 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 4: Metachronous Low Volume mHSPC

Case Presentation: A 76-year-old male with an ECOG performance status of 1 has a known history of prostate cancer Gleason Score 7 (4+3) in 5/12 cores and had previously undergone a robotic radical prostatectomy nine years ago with evidence of cT3a disease and positive surgical margins. After the patient had achieved urinary continence 6 months post-operatively, he and his treating physician opted for adjuvant radiation therapy to the prostatic fossa. The patient was free of biochemical recurrence until 5 years ago when his PSA was noted to progressively increase with a PSA doubling time of 18 months. A shared decision between the patient and physician was taken to forgo systemic therapy with androgen deprivation therapy until there was evidence of metastatic disease. At a serum PSA level of 5.2 ng/ml, a staging work up with a Pylarify PSMA PET/CT scan demonstrated evidence of a single metastatic site at the level of the 3rd lumbar vertebra. There was no evidence of any other metastatic sites (bone or visceral) and the patient’s blood work was otherwise unremarkable.

Doublet Therapy: Docetaxel + ADT

Importantly, there is consistent evidence against the use of docetaxel in this mHSPC subgroup. Results from the CHAARTED trial demonstrated a minimal overall survival in this subgroup (HR: 0.77; 95% CI: 0.51 to 1.18).5 Furthermore, results from the STOPCaP meta-analysis presented at ASCO 2022 using CHAARTED and GETUG-AFU15 data demonstrated no overall survival benefit to docetaxel addition (HR: 1.07; 95% CI: 0.75 to 1.54).

figure-10-mHSPC-cases2x.jpg

Doublet Therapy: ARAT + ADT

Subgroup analyses have consistently demonstrated an overall survival benefit to ARAT addition in patients with low volume mHSPC. Results from the ARCHES trial demonstrated a 37% improved hazard of overall survival with enzalutamide addition to ADT in patients with metachronous low volume mHSPC (HR: 0.63, 95% CI: 0.26 to 1.54).12 Analysis from the ENZAMET trial presented at ASCO 2022 demonstrated that this benefit is reflected in an improvement in 3-year overall survival from 83% to 92% on interim analysis.

Metastasis-Directed Therapy

In addition to systemic therapy with ADT + ARAT in this subgroup, there is emerging data from both ORIOLE, STOMP, and SABRC-COMET regarding the role of metastasis-directed therapy (MDT) in select patients with metachronous, oligometastatic mHSPC.

The STOMP trial was a multicenter, randomized phase II trial that prospectively evaluated the effects of MDT for patients with evidence of oligometastatic disease on choline PET/CT (up to three extracranial sites) who had received prior treatment with curative intent and had evidence of biochemical recurrence with testosterone >50 ng/ml (i.e. metachronous, oligometastatic mHSPC). Between 2012 and 2015, 62 patients were randomized 1:1 and MDT was either SBRT or metastasectomy. The primary endpoint was time to initiation of ADT (called ADT-free survival). ADT was initiated for symptoms, progression beyond three metastases, or local progression of known metastatic disease. Time to castration resistance was a secondary endpoint (called CRPC-free survival). The updated five-year results were presented at GU ASCO 2020. With a median follow up of 5.3 years, the five-year ADT-free survival was 8% in the surveillance arm compared to 34% for the MDT group (HR 0.57, 95% CI 0.38 to 0.84, log-rank p=0.06). Secondary endpoint of CRPC-free survival at 5 years was 53% in subjects under surveillance and 76% in those receiving MDT (HR 0.62, 80% CI 0.35 to 1.09).15


The ORIOLE trial was a randomized phase II trial of 54 men with metachronous, oligometastatic mHSPC (up to three sites). Metastatic sites were diagnosed via 18F-DCFPyL PET/CT. Between 2016 and 2018, patients were randomized in a 2:1 fashion to receive SABR or observation. The primary outcome was progression at 6 months, defined as serum PSA increase, progression detected by conventional imaging, symptomatic progression, ADT initiation for any reason, or death. Progression at six months occurred in 7 of 36 patients (19%) receiving SABR and 11 of 18 patients (61%) undergoing observation (p = 0.005). Treatment with SABR improved median PFS (not reached vs 5.8 months; HR 0.30, 95% CI 0.11 to 0.81).16
Recently published pooled data from the two trials demonstrates that MDT in these patients improves progression-free survival from 5.9 months (95% CI: 3.2 – 7.1) to 11.9 months (95% CI: 8.0 – 18.3; HR: 0.44, p<0.001), without any significant improvements seen in radiographic progression-free survival, time to castration-resistant disease, or overall survival.17


SABR-COMET was a randomized, open-label phase II study of patients with oligometastatic disease (up to five sites) between February 2012 and August 2016. This trial was not restricted to patients with prostate cancer and also included lung, breast, and colorectal cancer patients. Of the 99 patients in this trial, 18 (18%) had prostate cancer. After stratifying by the number of metastases (1–3 vs 4–5), patients were randomized in a 1:2 fashion to receive either palliative standard of care alone or standard of care plus SABR. In an updated analysis published in 2020 (median follow up 51 months), the five-year OS rate was 17.7% (95% CI 6-34%) in the control arm and 42.3% in the SABR arm (95% CI 28-56%, stratified log-rank p=0.006). The corresponding median OS was 28 months and 50 months, respectively.18
 

The following table summarizes OS outcomes by CHAARTED disease volume criteria and presentation (synchronous vs metachronous) among men with mHSPC:

table-1-mHSPC-cases2x.jpg

Treatment with ADT alone is no longer an adequate standard of care treatment for patients with mHSPC. Early treatment intensification with an ARAT and/or docetaxel is critical to maximize overall survival outcomes in mHSPC patients. Based on the current evidence, it appears that patients with synchronous, high volume mHSPC benefit from early treatment intensification with triplet therapy in the form of both an ARAT and docetaxel, whereas the remaining mHSPC subgroups benefit most from doublet therapy with ARAT addition to ADT. Radiotherapy to the prostate is associated with improved overall survival in mHSPC patients with synchronous, low-volume disease, whereas metastasis-directed therapy may be associated with improved outcomes in men with metachronous, oligometastatic disease.

figure-11-mHSPC-cases2x.jpg

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
References:
  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 https://seer.cancer.gov/statfacts/html/prost.html. 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.
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