CUOS 2019: Is There a Role for Treating the Primary in Metastatic Hormone-sensitive Prostate Cancer

Toronto, Ontario ( Dr. Robert Hamilton presented on the role of treatment of the primary tumor in the setting of metastatic hormone-sensitive prostate cancer (mHSPC).  He began his discussion providing the rationale for treating the primary tumor in mHSPC patients. This involves both clinical and biological factors. The biologic factors include:

  1. Aggressive clones can be identified in the prostate after systemic therapy.1
  2. Intact primary tumor can serve as a constant supply of metastatic cells
  3. Through secreted cytokines and growth factors, the primary tumor can prime distant metastatic niches to encourage implantation.
  4. Mouse metastatic prostate cancer models support the removal of the primary tumor
Additionally, there are clinical factors supporting this concept of treating the primary tumor:

1. Patients are currently living longer with new systemic therapies
2. Local symptoms are problematic in the late stages of the disease if they are left untreated.
3. This is an already an accepted paradigm in other cancers (kidney, breast and ovarian)
4. With changing PSA screening practices, more men present with metastases, increasing the role of controlling the primary tumor.

There are retrospective data demonstrating the benefit of this approach of removing the primary tumor. In a SEER-Medicare population-based analysis, factors that were associated with worse cancer-specific mortality in mHSPC patients included age >=70, Gleason score >=8 or clinical stage T4, N+.2 Another study compared androgen deprivation therapy (ADT) alone to ADT + radical prostatectomy (RP) in patients with less than three osseous metastases and no visceral metastases.3  The results demonstrated an improved median time to castrate-resistant prostate cancer (40 vs. 29 months, p=0.014) for the surgically treated patients, and a longer median time of cancer-specific survival (47 vs. 40 months, p – not significant). Similar improved results were shown when radiotherapy was used instead of radical prostatectomy in a retrospective study.4

Dr. Hamilton moved on to discuss some of the already published and ongoing randomized controlled trials in this setting (Figure 1). Two completed trials were selected and discussed. The first was the HORRAD trial, comparing radiotherapy + ADT to ADT alone, showing no significant differences in overall survival.5 Even when the authors performed stratification according to the burden of disease, no difference was seen in patients with high-burden and low-burden metastatic disease. However, another prospective study recently published was the STAMPEDE trial, comparing ADT + radiotherapy to the primary tumor, vs.  ADT alone.6 The results in this trial demonstrated no benefit to radiotherapy in the overall survival cohort (HR 0.92 95% CI 0.8-1.06, p=0.266). However, in a pre-specified subgroup analysis, the results showed improved overall survival in favor of the radiotherapy group in a specific group of patients with low-burden metastases (HR 0.68, 95% CI 0.52-0.9, p=0.007). No such benefit was shown in the high-burden metastases group.

Figure 1 – Prospective Trials Assessing the Role of Treatment of the Primary Tumor in Metastatic Patients:
UroToday CUOS19 the Role of Treatment of the Primary Tumor in mHSPC

This result raises the question whether the shown benefit is practice changing or only hypothesis changing. According to Dr. Hamilton, this subgroup analysis meets three basic rules to make it a credible practice-changing finding (according to a paper published in the British Medical Journal).7 These basic rules include:

  1. The fact that prior probability of subgroup effect was estimated at >20%
  2. Only one or two primary categorical subgroups exist
  3. The statistical power needs to be high, and the subgroup analysis needs to be specified a priori.
Before concluding his talk, Dr. Hamilton debated whether these results would be demonstrated if surgery was used instead of radiotherapy. Retrospective data suggest that radical prostatectomy is as good as radiotherapy, perhaps even better, but these data are highly biased. To date, there is no prospective head to head data in metastatic disease. The current best evidence supports the use of radiotherapy only. However, there are several reasons why we should still consider surgery as an option:

  1. Surgery in properly selected patients is feasible and safe.
  2. Erectile function is less a concern in these patients, as all are concomitantly treated with ADT.
  3. A thorough node dissection may control the pelvis better
  4. Surgery may minimize the risk of local complications, especially since patients are living longer
  5. No prostate cancer clone is resistant to steel (but could be resistant to radiotherapy)
  6. Radioresistant clones can seed future metastases even with systemic therapy.
In summary, according to Dr. Hamilton, the clinical and biological rationale for treating the primary tumor in mHSPC is strong. Retrospective data are supportive of this concept, and current prospective trials support the use of radiotherapy in patients with low-burden metastatic disease. To date, there is still not enough data to suggest that radical prostatectomy is as good as radiotherapy in this specific setting. The challenges that we face ahead include patient selection, and ascertainment of whether this paradigm will change with the optimal modern era systemic therapy used for mHSPC.

Presented by: Robert J. Hamilton, MD, MPH, FRCSC, Cancer Clinical Research Unit, Princess Margaret Cancer Center

Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre, Twitter: @GoldbergHanan at the CUOS – Canadian Uro-Oncology Summit 2019, #CUOS19 January 10-12, 2019 Westin Harbour Castle, Toronto, Ontario, Canada

1. Tzelepi, JCO 2011
2. Culp SH. Et al.  Eur Urol 2014
3. Heidenreich A. et al. Eur Urol 2015
4. Rusthoven Chad G. et al. JCO 2016
5. Boeve LMS et al.  European Urology 2018
6. Parker CC et al. The Lancet 2018
7. Burke JF. et al. The BMJ 2015