ASTRO 2021: Systemic Therapy for Very High Risk to Oligometastatic Prostate Cancer

( The American Society for Radiation Oncology’s 2021 annual meeting included an educational session discussing multidisciplinary management of very high-risk prostate cancer and a presentation by Dr. Alicia Morgans highlighting systemic therapy for very high-risk to oligometastatic prostate cancer. Dr. Morgans started by highlighting the disease characteristics according to the NCCN guidelines for high and very-high risk disease:

  • High Risk – has no very-high risk features and has exactly one high-risk feature:
    • cT3a, or
    • Grade Group 4 or Grade Group 5, or
    • PSA > 20 ng/mL
  • Very-High Risk – Has at least one of the following:
    • cT3b-cT4
    • Primary Gleason pattern 5
    • 2 or 3 high-risk features
    • >4 cores with Grade Group 4 or 5

As recently as September 2021, the NCCN guidelines now include the utilization of PSMA PET scans. Ga-68 PSMA-11 or F-18 piflufolastat PSMA PET/CT or PET/MRI can be considered for bone and soft tissue (full body) imaging. Additionally, because of the increased sensitivity and specificity of PSMA-PET tracers for detecting micrometastatic disease compared to conventional imaging (CT, MRI), at both initial staging and biochemical recurrence, the NCCN Panel does not feel that conventional imaging is a necessary prerequisite to PSMA-PET. PSMA-PET/CT or PSMA-PET/MRI can serve as an equally effective, if not more effective front-line imaging tool for these patients. It is important to note that stage migration (negative CT scan, positive PSMA PET/CT) is common with Ga-68 PSMA-11 PET/CT scans in the staging algorithm of men with high-risk localized disease, which has been highlighted in the proPSMA trial.1 The NCCN Guidelines Version 1.2022 for high- or very-high risk prostate cancer are as follows:


Dr. Morgans highlighted that several contemporary (albeit small) neoadjuvant surgical trials have been published, including a neoadjuvant abiraterone trial, a neoadjuvant enzalutamide trial, and a neoadjuvant abiraterone/enzalutamide trial. Pathologic complete response rates from these trials ranged from 4%-10%, and minimum residual disease rates ranged from 17%-30%. Biochemical recurrence rates are affected by minimum residual disease, highlighted by McKay et al. in a trial of 72 patients.2 Among these patients, 11 (15.7%) had <= 0.5 cm residual disease after neoadjuvant ADT combination therapy with none of these patients experiencing a biochemical recurrence.

The CALGB 90203 PUNCH trial was published in 2020 [3], randomizing men to radical prostatectomy alone or neoadjuvant chemohormonal therapy with androgen deprivation plus docetaxel + radical prostatectomy. Patients were stratified according to nomogram prediction of biochemical progression free survival at 5-years or Gleason 8-10 disease and pre-randomization ADT (up to 4 months permitted). Adjuvant radiation therapy was also permitted within 6 months of radical prostatectomy. The trial schema is as follows:


In PUNCH, there was no difference in 3-year biochemical progression free survival between the groups (0.89 vs 0.84, p = 0.11), however, neoadjuvant chemotherapy was associated with improved metastasis-free survival (HR 0.70, 95% CI 0.51-0.95) and overall survival (HR 0.61, 95% CI 0.40-0.95). The PROTEUS trial is a phase 3 study of apalutamide in men with high-risk, localized, or locally advanced prostate cancer and is currently awaiting results read-out. PROTEUS is randomizing high-risk men to an LHRH agonist + 6 months of apalutamide followed by radical prostatectomy versus LHRH agonist followed by radical prostatectomy. The co-primary endpoints are pathologic complete response and metastasis free survival. The trial schema for PROTEUS is as follows:


Dr. Morgans also highlighted several adjuvant surgical trials, including the phase 3 randomized Veterans Affairs Cooperative Studies Program Study 553, assessing chemotherapy after prostatectomy for high-risk prostate cancer.4 Unfortunately, this trial failed to reach the planned accrual of 636 patients, only accruing 296 patients. Six cycles of adjuvant docetaxel in men with clinically identified high-risk localized prostate cancer were not associated with improved progression free survival. Currently ongoing is the ERADICATE trial, assessing early intervention after radical prostatectomy with androgen deprivation therapy with darolutamide versus placebo in men at highest risk of metastasis by genomic stratification. The trial schema for ERADICATE is as follows:


Several trials have also assessed intensified systemic therapy in radiation trials. The randomized phase III NRG Oncology RTOG 0521 trial assessed the effect of chemotherapy with docetaxel with androgen suppression and radiotherapy for localized high-risk prostate cancer.5 Patients were randomly assigned to receive standard long-term androgen suppression plus radiotherapy with or without adjuvant chemotherapy. A total of 612 patients were enrolled and 563 were evaluable. Over a median follow-up of 5.7 years, the four-year OS rate was 89% (95% CI, 84% to 92%) for androgen suppression plus radiotherapy and 93% (95% CI, 90% to 96%) for androgen suppression plus radiotherapy plus chemotherapy (HR 0.69, 90% CI, 0.49 to 0.97; one-sided p = 0.034):


Presented at ESMO 2021 was the combined analysis from two comparisons in the STAMPEDE platform assessing standard of care (radiotherapy plus 3 years of ADT) to standard of care plus abiraterone acetate + prednisolone with or without enzalutamide for two years. With six years of median follow-up, there was a 47% reduction in metastasis free survival for the addition of abiraterone acetate + prednisolone with or without enzalutamide to standard of care (p = 2.9 x10^-11). This translated to six-year metastasis free survival of 82% on the standard of care plus abiraterone acetate + prednisolone with or without enzalutamide compared to 69% on the standard of care arm:


Additionally, with six years of median follow-up, there was a 40% reduction in OS for the addition of abiraterone acetate + prednisolone with or without enzalutamide to standard of care (p = 9.3 x10^-7). This translated to six-year OS of 86% on the standard of care plus abiraterone acetate + prednisolone with or without enzalutamide compared to 77% on the standard of care arm. As seen with metastasis free survival, there was no significant difference in OS across randomization periods, further supporting no additional improvement with the addition of enzalutamide to abiraterone acetate + prednisolone:


Dr. Morgans concluded her presentation of systemic therapy for very-high risk prostate cancer with the following take-home messages:

  • Multidisciplinary treatment including a combination of systemic therapy, radiation, and surgery offers patients with high-risk disease new hope for long term disease control and potential cure
  • Accurate risk stratification (+/- PET?) is critical to maximizing disease control and reduce risk complications
  • Neoadjuvant and adjuvant systemic treatment is still being evaluated in combination with local treatment
  • ADT + abiraterone for 2-years with radiation in men with very high-risk localized disease prolongs metastasis free survival and overall survival versus ADT alone

Presented by: Alicia Morgans, MD, MPH, Medical Oncologist, Dana Farber Cancer Institute, Boston, MA

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2021 American Society for Radiation Oncology (ASTRO) Hybrid Annual Meeting, Sat, Oct 23 – Wed, Oct 27, 2021.


  1. Hofman MS, Lawrentschuk N, Francis, RJ, et al. Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): A prospective, randomized, multicentre study. Lancet 2020 Apr 11;395(10231):1208-1216.
  2. McKay RR, Montgomery B, Xie W, et al. Post prostatectomy outcomes of patients with high-risk prostate cancer treated with neoadjuvant androgen blockade. Prostate Cancer Prostatic Dis. 2018 Sep;21(3):364-372.
  3. Eastham JA, Heller G, Halabi S, et al. Cancer and Leukemia Group B 90203 (Alliance): Radical Prostatectomy With or Without Neoadjuvant Chemohormonal Therapy in Localized, High-Risk Prostate Cancer. J Clin Oncol. 2020 Sep 10;38(26)3042-3050.
  4. Lin DW, Shih MC, Aronson W, et al. Veterans Affairs Cooperative Studies Program Study #553: Chemotherapy After Prostatectomy for High-risk Prostate Carcinoma: A Phase III Randomized Study. Eur Urol. 2020;77(5):563-572.
  5. Rosenthal SA, Hu C, Sartor O, et al. Effect of Chemotherapy with Docetaxel with Androgen Suppression and Radiotherapy for Localized High-Risk Prostate Cancer: The Randomized Phase III NRG Oncology RTOG 0521 Trial. J Clin Oncol. 2019 May 10;37(14):1159-1168.
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