ORIOLE Trial Update
Metastatic disease at the time of prostate cancer diagnosis accounts for about 20 percent of cases worldwide. An important challenge in prostate cancer treatment concerns how we should classify and treat ‘oligometastatic’ tumors. This stage of prostate cancer progression refers to a type of metastasis where a small number of new, metastatic tumors have become established beyond the localized primary tumor. Generally, the number is defined by imaging as five or fewer, and represents an intermediate state between the localized, primary tumor, and widespread metastatic disease with many sites. However there is still disagreement about exactly how to define the stage, in part because the different metastatic sites may not share exactly the same tumor cell clones; some may be aggressive whereas others may be indolent. This oligometastatic stage is treatable, and often still androgen-sensitive, so effective approaches have included androgen-deprivation therapy (ADT) alone or in combination with chemotherapy, or radiation of the prostate. Clinical trials have shown that combining several treatment approaches in multimodality therapy can achieve lasting benefit.
Men who have oligometastatic prostate cancer may wish to delay initiation of androgen deprivation therapy, and consider specialized types of radiation therapy, especially where the number of metastatic sites outside the prostate are few. Stereotactic ablative radiotherapy (SABR) provides a high dose of radiation in a tightly focused area where the metastatic lesion is located, to eliminate the tumor cells while limiting the dose to nearby normal tissues. This approach is effective, accurate and convenient for the patient. The field has been evaluating how well this type of radiation therapy works for patients with oligometastatic disease, and the Observation vs. Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer (ORIOLE) trial has been active in a Phase 2 randomized study. Results were reported in late March 2020 for participants from three US radiation treatment facilities affiliated with a university hospital from May 2016 to March 2018 with a data cutoff date of May 20, 2019, for analysis. Of 80 men screened, 54 men with recurrent hormone-sensitive prostate cancer and one to three metastases detectable by conventional imaging who had not received ADT within six months of enrollment or three or more years total were randomized (Phillips et al. JAMA Oncol. 2020;6(5):650-659. doi:10.1001/jamaoncol.2020.0147).
The primary outcome of the trial was progression at six months by prostate-specific antigen (PSA) level increase, progression detected by conventional imaging, symptomatic progression, ADT initiation for any reason, or death. Predefined secondary outcomes were toxic effects of SABR, local control at six months with SABR, progression-free survival, Brief Pain Inventory (Short Form)–measured quality of life, and concordance between conventional imaging and prostate-specific membrane antigen (PSMA)–targeted positron emission tomography (PET) in the identification of metastatic disease. Of the 54 men, progression of disease at six months occurred in 7 of 36 participants (19%) treated with SABR and in 11 of 18 participants (61%) undergoing observation, a statistically significant difference (P = .005). Treatment with SABR improved median progression-free survival (not reached vs 5.8 months; hazard ratio, 0.30; 95% CI, 0.11-0.81; P = .002). Total consolidation of PSMA radiotracer-avid disease decreased the risk of new lesions at 6 months (16% vs 63%; P = .006). No toxic effects of grade 3 or greater were observed.
From this Phase 2 trial result, it is reasonable to conclude that SABR is a promising treatment approach for men with recurrent hormone-sensitive oligometastatic prostate cancer who wish to delay initiation of androgen deprivation therapy. In addition, significant changes were observed in the T cells of patients on the SABR arm 90 days after treatment, but no change in the T cells of those in the observation arm. It is possible that the radiation dose may prime the immune system to tumor antigens and increase the anti-tumor CD8+ T cell response. This result would be encouraging because most prostate tumors are considered immunologically ‘cold’, with little immune involvement that could help reduce tumor burden. For this reason, immune checkpoint blockade therapies that have been successful in highly immunogenic tumors like melanoma have been disappointing in prostate cancer. Based on the ORIOLE trial result, possible combinations of SABR with immune checkpoint blockade may be warranted in future clinical trials.