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High-dose radiation effective in oligometastatic prostate cancer
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Stereotactic ablative radiation appeared to be an effective and safe treatment for men with oligometastatic prostate cancer, with significant benefits observed in terms of 6-month freedom from progression and PFS, according to results of the randomized phase 2 ORIOLE study presented at American Society of Radiation Oncology Annual Meeting.
Although data support the safety and efficacy of high-dose radiation for men with localized or nonmetastatic prostate cancer, patients with oligometastatic disease usually are considered incurable.
“Single-institution studies and limited prospective data have recently suggested that high-dose, targeted radiation may be effective for men whose prostate cancer had spread, and now these ORIOLE randomized data confirm those observations,” Ryan Phillips, MD, PhD, chief resident in radiation oncology at Johns Hopkins School of Medicine, said in a press release. “Compared [with] retrospective reports, our study provides a higher level of evidence that stereotactic ablative radiation (SABR) benefits these patients because we can see how the patients who didn’t get SABR did in comparison.”
Research has suggested that SABR may be effective for other types of oligometastatic cancer, meaning the cancer has returned to a limited number of disease sites, but its effectiveness for oligometastatic prostate cancer had not been determined.
Phillips and colleagues randomly assigned 54 patients with recurrent hormone-sensitive oligometastatic prostate cancer — who were stratified based on primary management, PSA doubling time and prior androgen deprivation therapy — to undergo SABR (n = 35) or observation (n = 19).
Progression at 6 months by PSA — defined as a 2 ng/mL or greater increase and a level at least 25% above the nadir — conventional imaging, symptomatic decline or initiation of ADT served as the primary endpoint.
Results showed that progression at 6 months occurred among 19% of patients in the SABR group compared with 61% of patients in the observation group (P = .005).
Median PFS was not reached in the SABR group and was 5.8 months for men who underwent observation (HR = 0.3; 95% CI, 0.11-0.81).
Patients in the SABR group also underwent prostate-specific membrane antigen (PSMA)-based PET/CT scans at baseline and 6 months, a more sensitive imaging technology that detects proteins overexpressed in prostate cancer and can reveal tumor growth that may be undetectable by conventional imaging. Results of these scans were used for additional analysis and comparison of cancer growth, but not to determine treatment plans.
Results showed patients in total consolidation — meaning they had no additional untreated lesions detected by PSMA PET — were less likely to develop new lesions at 6 months (16% vs. 63%; P = .006). They also had significantly longer median PFS (unreached vs. 11.8 months; P = .003) and longer distant metastasis-free survival (29 months vs. 6 months; P = .0008) than patients whose PSMA PET scan showed additional lesions at baseline.
“Patients with subtotal consolidation had more new lesions. It isn’t just that the untreated lesions are continuing to grow,” Phuoc Tran, MD, PhD, associate professor of radiation oncology and molecular radiation sciences at Johns Hopkins Kimmel Cancer Center, said in the press release. “Other studies have made similar observations, but these are probably the most robust, sensitive and controlled observations that SABR can excite a systemic immune response.”
Deep sequencing of T-cell receptor DNA showed significantly more clonotypic expansions between baseline and day 90 for patients in the SABR group compared with the observation group (P = .03).
“These data suggest SABR seems to be inducing some sort of systemwide immune response, similar in scope to what we see after a vaccination,” Phillips said during a press conference.
Researchers also evaluated circulating tumor DNA and identified a mutational signature that predicted benefit from SABR. When they looked at high-risk mutations associated with poor prognosis in prostate cancer, they found that men with at least one high-risk mutation prior to treatment had similar outcomes whether they underwent SABR or observation. However, men without high-risk mutations had significantly better outcomes with SABR than observation (P = .011).
“These are low-sample size, hypothesis-generating experiments, but it is promising that there may be measurable baseline factors that will help us decide which patients are likely to benefit from this approach, and which would be better served with an alternate treatment strategy,” Phillips said.
No grade 3 or higher toxicities occurred throughout the trial.
“There is now accumulating evidence that SABR is effective for patients with oligometastatic disease, but there are currently no biomarkers that help us to determine who benefits most from this treatment,” Max Diehn, MD, PhD, associate professor of radiation oncology at Stanford University, said in the press release. “Our findings represent the first molecular marker that may predict a benefit of SABR in patients with oligometastatic disease. If additional validation of this mutational signature bears out in other cohorts, then we could potentially use it to personalize which patients with oligometastatic prostate cancer should receive SABR.”– by John DeRosier
Reference:
Phillips R, et al. Abstract LBA3. Presented at: ASTRO Annual Meeting; Sept. 15-18, 2019; Chicago.
Disclosures: Phillips reports a consultant role with RefleXionMedical Inc. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Mark A. Hallman, MD, PhD
There is increasing evidence that radiation therapy may offer more than just symptom palliation for patients with metastatic cancers. In particular, increasing evidence suggests that treatment of oligometastatic lesions with SABR also may improve disease control. Recent clinical trials suggest that ablative treatment of oligometastses improves PFS and may also improve OS — a role previously limited to systemic therapies.
These results from the ORIOLE trial add to the previous results of the STOMP trial that suggest this approach may become a future standard of care for men with newly diagnosed oligometastatic prostate cancer. Researchers of the STOMP trial randomly assigned men with one to three oligometastases 1:1 to observation or metastases-directed therapy (MDT), including SABR, with the goal to double the time to initiation of ADT to 2 years. Indeed, the median time to ADT initiation increased from 13 months with observation to 21 months with MDT.
The ORIOLE trial now explores SABR among a similar population of men with newly diagnosed recurrent prostate cancer and one to three metastases identified with conventional imaging (CT, MRI or bone scan). Results showed PFS improved to 29 months among men treated with SABR vs. 6 months among men under observation. SABR also was well-tolerated. In addition, researchers investigated several exploratory endpoints, including PSMA PET, circulating tumor DNA and T-cell characterization.
The ORIOLE trial adds to mounting evidence for an expanding role of SABR to potentially improve overall disease control for patients with oligometastatic prostate cancer. These exciting results support further investigation in phase 3 trials and to compare SABR with best systemic therapy. The inclusion of advanced diagnostic imaging and potential predictive biomarkers is likely to aid treatment personalization and appropriate patient selection.
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