The incidence of metastatic prostate cancer at diagnosis, i.e., metastatic hormone-sensitive prostate cancer has increased, partly due to the fallout from the 2012 Task Force recommendation against screening, particularly increasing in men older than 75 years. This increase also likely resulted from the application of the more sensitive Ga68-PSMA-11 and Pylarify PET/CT scans. These newer scans have the accuracy of imaging tumors larger than ~ .5 cm, often missed on conventional CT and technetium bone scans. Staging cancer prior to initial treatment is appropriate in men with unfavorable-risk intermediate and high-risk cancer. Multiple studies have shown that the results of these scans change the originally proposed treatment plans in approximately 50% of instances. The detection of disease beyond the prostate increases in these scans as the PSA and Gleason Score rise. 

 › PSMA Targeted PET/CT Scans in Men with Advanced Cancer Increases the Diagnosis of Metastatic Cancer.

 Hoffman et al., Lancet 2020, using PSMA imaging found pelvic nodal or distant metastases in 29% of 295 men with high-risk cancer — a 27% greater detection accuracy than conventional CT scanning. Distant metastases at diagnosis were found in 21% of men while only identified in 7% on CT imaging.

 Simsek et al., Eur J Nucl  Med Mol Imaging, Aug 2020, also employing the 68Ga-PSMA-11 PET/CT,  scanned 356 men with median Gleason scores of > 8 and detected lymph node spread in 35% with 13% beyond the pelvis, bone metastases in 25.6% and visceral lesions in 4.7%. 

 The treatment options for those men with extra-pelvic nodal, skeletal, or visceral disease (mHSPC) is the subject of this Commentary. Three major reviews will be discussed.


  1. Radiotherapy to the Prostate for Men with mHSPC: Long-term results from the STAMPEDE trial. (Based on Parker et al., PLOS Medicine, June 2022.)

 The 2061 trial participants in this study were subdivided into two cohorts based on CT, MRI, and bone scan imaging.

  •  High-burden disease was defined as “polymetastatic > 4 bone metastases with > 1 outside the vertebral bodies or pelvis, and/or visceral metastases.”
  •  Low burden was defined as oligometastatic, i.e., < 3 metastatic lesions. “Patients with only lymph node metastases, in the absence of bone or visceral disease, were classified as low metastatic burden regardless of the number of nodal metastases.” (Parker, ibid)

 The Parker Study and Its Findings:

 Two cohorts were studied: 1029 men were treated with standard-of-care (SOC) ADT and compared to 1032 men who received SOC plus hypofractionated radiation to the prostate (e.g.,CyberKnife). Later in the trial docetaxel chemotherapy was added to SOC. Each group was analyzed as to tumor burden — low or high. Follow-up was 61.3 months. Both arms were evenly matched with 17-18% having < 7 Gleason Score and 82-83% with Gleason Score 8-10. Forty-two percent were low burden and 58% high.


  •  Overall survival in the low burden group was 85.5 months (prostate irradiated) vs 63.6 months (no radiation); 5-year survival was 65% in men with irradiated low-burden disease, vs 53%, no radiation.
  •  There was no statistical survival benefit for prostate radiation in the high-burden arm — 38-41 months;  5-year survival 30-35 months.


 2. Systemic Treatment Only for mHSPC: A Review

A systematic review was compiled by Wenzel et al., “Overall Survival After Systemic Treatment in High-volume Versus Low-volume Metastatic Hormone-sensitive Prostate Cancer”, Eur Urol  Focus, 2022. The distinction,  high- or low-volume disease has been accepted into the NCCN guidelines. The summation in Wenzel is based on a meta-analysis of five major randomized trials and reported in terms of median overall survival (mOS). 


  •  In high-volume disease the mOS for Zytiga+ADT vs docetaxel+ADT vs ADT alone was 1 vs  45.9  vs 34 months, respectively. These values were reproducible in both the American and European studies.
  •  In the low volume meta-analysis Zytiga+ADT was clearly superior to docetaxel+ADT. Docetaxel treatment in low volume mHSPC resulted in a mOS of 69.5 mo versus 67.7 mo with ADT alone.


3. Triple Drug Therapy for mHSPC: The ARASENS Trial (Smith et al, “Darolutamide and Survival in Metastatic Hormone-Sensitive Prostate Cancer,” NEJM Feb 2022).

 The study randomized 1173 men with mHSPC between darolutamide/ADT/docetaxel or ADT/docetaxel. mHSPC was based on CT, MRI, and bone scans. The men had advanced disease: 78.6% had Gleason Score > 8; bone metastases and/or lymph node metastases were diagnosed in 79.4%. The mPSA was 30.3 in the triple therapy arm vs 24.2 in the docetaxel/ADT arm.

 The participants were stratified as to location of metastases, but survival was not reported using the classification  low- vs high-burden diseases, so there was “limited information” regarding survival in men with a better prognosis and a lesser disease burden. No radiation was administered to the prostate. 


  •  Median overall survival for triple therapy at 4 years was 62.7% and for docetaxel/ADT 50.4%.
  •  Time to the development of castration resistance “was significantly longer in the darolutamide group, [improved by 36%]. The need for additional systemic therapy was delayed in the triple therapy group. “Serious adverse effects” occurred equally ~ 42-45%, but that rate of adverse effects is significant and largely due to docetaxel.


› Take Aways: Many Treatment Options – Ample Opportunity for Individualized Management:

 It is not appropriate to try to derive a “best” therapy of mHSPC from these three major trials  … there are too many disparate elements in study designs. The range of potential treatment options extends from metastases directed radiation in oligometastatic cancer (treating the prostate and using  ADT or delaying it) to using the triple drug combination as reported by Smith in the NEJM. However, some features are ‘take-aways’.

  1.  For initial staging of advanced prostate cancer, the Ga68-PSMA PET/CT-11 and Pylarify scans have superior accuracy compared to conventional CT and bone scans and inform treatment decisions.
  2.  Although arbitrary, the classification of a patient’s presentation into low- and high-burden disease is a useful tool for individualizing treatment.
  3.  Darolutamide, a structurally distinct anti-androgen, has been shown to be effective with minimal penetration into the brain resulting in fewer cerebral adverse effects (falls, seizures, cognitive disorders, and mental impairment) than, for example, as seen enzalutamide treatment. (Fizazi et al, NEJM, 2020). 
  4.  In high-volume disease the combination of Zytiga+ADT yielded similar mOS to docetaxel+ADT, but a higher toxicity was associated with chemotherapy.  


 For the treatment of metastatic hormone-sensitive prostate cancer there are many available effective regimens.