SUO 2018: Treatment of the Primary Is Not Necessary, or Is It?

Phoenix, Arizona ( In this debate during the prostate cancer session, the two speakers look at the question of primary therapy for metastatic prostate cancer. Both ultimately agreed on the final message.
PRO: Brian Chapin, MD
First up was Dr. Chapin, the lead investigator on the SWOG 1802 and MD Anderson Best Systemic Therapy (BST) trials. He started by reviewing the rationale for local definitive therapy in the metastatic setting:

  1. Multiple retrospective series have demonstrated the overall survival (OS) benefit
  2. Local symptomatic progression is reduced by treatment of the primary
  3. Molecularly “lethal prostate cancer” persists in primary tumors despite systemic therapy and may serve as the nidus for recurrence
  4. Systemic tumor biology may be altered by removal of the primary
  5. Randomized trials are feasible and local treatment is safe
There are numerous clinical trials ongoing in this space – and this slide summarizes them pretty well:

The only two studies that have completed and reported are the HORRAD trial (Boeve et al. EU 2018) and the STAMPEDE trial (arm focusing on local therapy) (Parker et al. Lancet 2018). He briefly reviewed their results, which I highlight below – and Dr. Delacroix revisited later.

In the HORRAD trial, there was no OS benefit with the addition of RT to ADT for men with metastatic prostate cancer (p = 0.2). However, while most of the study was enriched with men with high volume metastatic disease, in the subset with <5 metastases, there was a suggestion of benefit – though not statistically significant (HR 0.68, CI 0.42-1.18).

In the STAMPEDE trial (ARM H), there was no OS benefit with the addition of RT to ADT for men with metastatic prostate cancer (p = 0.26). However, on sub-group analysis presented just this year, when split into low and high metastatic burden by CHAARTED criteria, men with a low burden of disease did have an OS benefit (HR 0.68, p = 0.007). Other markers of response were also significantly improved (failure-free survival, HR 0.59, p < 0.0001).

So, ultimately, the benefit is based on patient selection.

  1. Symptomatic local progression may be improved with treatment of the primary. It does not seem to be associated with RT addition to ADT, but primary surgical excision is associated with improved in reduced symptomatic local progression.
  2. There are biologically distinct subsets of prostate cancer with unique therapeutic vulnerabilities – for example, Androgen indifferent cancers may not respond to ADT alone.
They are currently completing a Phase II Trial of +/-  definitive therapy as MD Anderson – either RP or RT for definitive primary therapy. It is active, but no longer accruing. 119 patients were randomized. The primary endpoint is CRPC progression. They have numerous correlative studies ongoing simultaneously. Here are the demographics of some of the patients:

More importantly, they have now started enrolling in the SWOG S1802 Phase III clinical trial. The primary outcome is overall survival. Study protocol below:

Ultimately, he concludes the rationale is there and they patients should be enrolled in these clinical trials.

CON: Scott E. Delacroix, Jr., MD

On the opposite side, Dr. Delacroix made a strong argument that treatment of the primary is NOT standard of care based on current data.

He reviewed HORRAD and STAMPEDE and drove home the point that, at the end of the day, both were negatives studies! He also made it a point to criticize the STAMPEDE study as strong evidence as the stratification of low and high volume disease was added just 6 months before the data was published – but was not included in the original stratification. This was a point of contention by the authors of STAMPEDE, who were at the debate.

Regardless, the take-home point is that the currently published literature does NOT support primary therapy for metastatic disease. To get to the final theme of the debate, both essentially agreed that the rationale is there, but the current evidence doesn’t support it – so patients should be enrolled in clinical trials!

Presented by: PRO: Brian Chapin, MD, Department of Urology, Division of Surgery Division, MD Anderson Cancer Center and  CON: Scott E. Delacroix, Jr., MD, Director of Urologic Oncology, Associate Professor Department of Urology, Director of Cancer Pathology, Stanley S. Scott Cancer Center MBCCOP, LSU Healthcare Network Clinic

Written by: Thenappan Chandrasekar, MD, Clinical Instructor, Thomas Jefferson University, @tchandra_uromd, @TjuUrology, at the 19th Annual Meeting of the Society of Urologic Oncology (SUO), November 28-30, 2018 – Phoenix, Arizona