Dr. Ost notes that there are two trials that have assessed standard of care versus standard of care plus radiotherapy to the primary tumor: HORRAD,1 and STAMPEDE arm H.2 The HORRAD trial is a multicenter randomized control trial (RCT) recruiting 432 patients with PSA >20ng/ml and primary bone metastatic prostate cancer on bone scan between 2004 and 2014. Patients were randomized to either androgen deprivation therapy (ADT) with external beam radiation therapy (EBRT) (radiotherapy group) or ADT alone (control group). The primary endpoint was overall survival (OS), and the secondary endpoint was time to prostate-specific antigen (PSA) progression. Over a median follow-up of 47 months, the median overall survival was 45 months (95% CI, 40.4-49.6) in the radiotherapy group and 43 months (95% CI, 32.6-53.4) in the control group (p=0.40); there was no significant difference was found in overall survival (HR 0.90, 95% CI, 0.70-1.14; p=0.40)
Additionally, median time to PSA progression in the radiotherapy group was 15 months (95% CI 11.8-18.2), compared with 12 months (95% CI: 10.6-13.4) in the control group (HR 0.78, 95% CI 0.63-0.97, p=0.02). Importantly, Dr. Ost noted that in the subgroup analyses high burden metastatic patients (5-15 mets HR 1.18, 95% CI 0.74-1.89; >15 mets HR 0.93, 95% CI 0.66-1.32) did not benefit from the addition of radiotherapy.
In the STAMPEDE arm H trial, 2,061 men were randomized in a 1:1 ratio to standard of care (control group) or standard of care and radiotherapy (radiotherapy group). Men allocated radiotherapy received either a daily (55 Gy in 20 fractions over 4 weeks) or weekly (36 Gy in six fractions over 6 weeks) schedule. The primary outcome was overall survival, and secondary outcomes were failure-free survival, progression-free survival, metastatic progression-free survival, prostate cancer-specific survival, and symptomatic local event-free survival. There were 819 (40%) men that had a low metastatic burden, 1120 (54%) had a high metastatic burden, and the metastatic burden was unknown for 122 (6%). Radiotherapy improved failure-free survival (HR 0.76, 95% CI 0.68-0.84; p<0.0001) but not overall survival (0.92, 0.80-1.06; p=0.266). Importantly, overall survival in patients with low metastatic burden showed an improved survival benefit among patients receiving radiotherapy (HR 0.68, 95% CI 0.52-0.90, p=0.007):
There was no survival benefit among men with high burden metastatic disease (HR 1.07, 95% CI 0.90-1.28). The STOPCAP group subsequently performed a meta-analysis of these two trials: pooled results (2,126 men; 90% of those eligible) showed no overall improvement in survival (HR 0.92, 95% CI 0.81-1.04, p=0.195) or PFS (HR 0.94, 95% CI 0.84-1.05, p=0.238) with prostate radiotherapy. The effect of prostate radiotherapy varied by metastatic burden-a pattern consistent across trials and outcome measures, including survival (<5, ≥5; interaction HR 1.47, 95% CI 1.11-1.94, p=0.007). Dr. Ost reiterated that in patients with N1/M1a disease and/or <5 bone metastases on bone scintigraphy, irrespective of location, failure-free survival, and overall survival are improved with radiotherapy.
Dr. Ost highlighted that PSMA PET-CT imaging can change the management of patients. For example, in patients with conventional imaging M0 disease, treatment options may include radical prostatectomy or radiotherapy +/- ADT. If this patient were to get a PSMA PET-CT, they may be upstaged to low volume M1 disease, whereby treatment options may include radiotherapy + ADT, ADT + androgen receptor pathway inhibition, or ADT + docetaxel. Another example is for patients that are conventional imaging low volume M1 disease – treatment options may include radiotherapy + ADT, ADT + androgen receptor pathway inhibition, or ADT + docetaxel. If this patient receives a PSMA PET-CT, they may be upstaged to high volume M1 disease, whereby treatment options would include ADT + androgen receptor pathway inhibition or ADT + docetaxel.
Dr. Ost concluded his presentation with the following take-home messages:
- Prostate radiotherapy + ADT (+/- 6x docetaxel) improved OS and FSS in patients with only lymph node or <4 bone metastases regardless of location
- Open issues include how to combine with added systemic therapy and the role of PSMA PET-CT
Presented by: Piet Ost, MD, Ph.D., Radiation Oncologist, Ghent University Hospital, Ghent, Belgium
Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md at the 12th European Multidisciplinary Congress on Urological Cancers (EMUC) (#EMUC20 ), November 13th - 14th, 2020
References:
- 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 Mar;75(3):410-418.
- Parker CC, James ND, Brawley CD, et al. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): A randomized controlled phase 3 trial. Lancet 2018 Dec 1;392(10162):2353-2366.
- Burdett S, Boeve LM, Ingleby FC, et al. Prostate radiotherapy for metastatic hormone-sensitive prostate cancer: A STOPCAP Systematic Review and Meta-analysis. Eur Urol. 2019 Jul;76(1):115-124.