Metastases-directed therapy in addition to standard systemic therapy in oligometastatic castration resistant prostate cancer: A randomized phase II trial (GROUQ-PCS 9).

22 Background: Metastases directed therapy (MDT) in metachronous hormone sensitive prostate cancer (mHSPS) patients has been shown to delay systemic therapy and to a lesser extent improve oncological outcome. To date there has not been strong data to suggest benefit of MDT in castration resistant prostate cancer (CRPC). In this multi-centric randomized phase II trial, we sought to determine the benefit of stereotactic body radiotherapy (SBRT) in oligometastatic CRPC (omCRPC) patients. Methods: PCS-9 was originally designed as an adaptive randomized phase II/III trial conducted across 13 sites in Canada. Given that ARPIs became the standard of care in mHSPC, the study was stopped at the phase II level after 100 mCRPC patients, with 5 or less metastatic sites, were recruited. Patients were randomly assigned in a 1:1 ratio to androgen deprivation therapy (ADT) + enzalutamide (Enza), arm-1 or ADT + Enza + SBRT to the conventionally (CT/MRI/bone scan) identified oligometastatic sites, arm-2. The primary endpoint was radiological progression free survival (rPFS), defined as radiological progression or death from any cause. Results: Of the 100 omCRPC patients, 48 were randomized to ADT+Enza and 52 to ADT+Enza+SBRT. There was no difference in patient or disease characteristics. One to three metastases occurred in 89.6% of arm-1 and 84.6% of arm-2, while visceral involvement accounted for 2.1 and 5.8%, respectively. The addition of SBRT doubled the median rPFS compared to ADT and Enza alone. rPFS was 4.6 years in the SBRT group and 2.3 years in the ADT and Enza arm, a 50% risk reduction (HR: 0.5 with 95% CI, 0.28-0.88; p=0.017). Similarly, biochemical progression free survival (bPFS) was 4.5 years for the SBRT arm and 2.6 years for ADT and Enza alone arm, a 44% risk reduction (HR:0.56 95% CI, 0.31-0.99 p=0.0425). At the time of this analysis there was a 27% risk reduction of death with the addition of SBRT (HR:0.73; 95% CI, 0.33-1.64; p=0.463), however the median OS had not been reached for either arm. Time to subsequent therapy was significantly delayed by the addition of SBRT. The median time to subsequent therapy was 5.1 years for the SBRT arm vs. 3.8 years for the ADT + Enza alone arm, a risk reduction of 48% (HR:0.52; 95% CI, 0.27-0.047; p:0.047). There was no difference in adverse event between the arms including fatigue, hypertension and fracture. Only 4 patients in the SBRT arm reported transient pain flare at the SBRT site and one patient had acute asymptomatic pneumonitis. Conclusions: The addition of SBRT to oligometastatic sites in mCRPC significantly improved rPFS, improved bPFS and delayed the time to next line of therapy. Although OS remains immature, there was numerical reduction in the risk of death. These results strongly suggest that SBRT to oligometastatic sites is beneficial and should be considered in patients with oligo-metastatic CRPC. Clinical trial information: NCT02685397 .