Dr. Jonathan Tward
The score can identify patients in whom the risk of metastasis after dose-escalated radiation is so small that adding ADT no longer makes clinical sense, according to investigator Jonathan Tward, MD, PhD, of the Genitourinary Cancer Center at the University of Utah, Salt Lake City.
His group’s study, which included 741 patients, showed that, below a CCR score of 2.112, the 10-year risk of metastasis was 4.2% with radiation therapy (RT) alone and 3.9% with the addition of ADT.
“Whether you have RT alone, RT plus any duration of ADT, insufficient duration ADT, or sufficient ADT duration by guideline standard, the risk of metastasis never exceeds 5% at 10 years” even in high- and very-high-risk men, Dr. Tward said.
He and his team found that half the men in their study with unfavorable intermediate-risk disease, 20% with high-risk disease, and 5% with very-high-risk disease scored below the CCR threshold.
This implies that, for many men, ADT after radiation “adds unnecessary morbidity for an extremely small absolute risk reduction in metastasis-free survival,” Dr. Tward said at the 2021 Genitourinary Cancers Symposium, where he presented the findings (Abstract 195).
Value of CCR
The CCR score tells you if the relative metastasis risk reduction with ADT after radiation – about 50% based on clinical trials – translates to an absolute risk reduction that would matter, Dr. Tward said in an interview.
“Each patient has in their own mind what that risk reduction is that works for them,” he added.
For some patients, a 1%-2% drop in absolute risk is worth it, he said, but most patients wouldn’t be willing to endure the side effects of hormone therapy if the absolute benefit is less than 5%.
The CCR score is a validated prognosticator of metastasis and death in localized prostate cancer. It’s an amalgam of traditional clinical risk factors from the Cancer of the Prostate Risk Assessment (CAPRA) score and the cell-cycle progression (CCP) score, which measures expression of cell-cycle proliferation genes for a sense of how quickly tumor cells are dividing.
The CCP test is available commercially as Prolaris. It is used mostly to make the call between active surveillance and treatment, Dr. Tward explained, “but I had a hunch this off-the-shelf test would be very good at” helping with ADT decisions after radiation.
‘Uncomfortable’ findings, barriers to acceptance
“People are going to be very uncomfortable with these findings because it’s been ingrained in our heads for the past 20-30 years that you must use hormone therapy with high-risk prostate cancer, and you should use hormone therapy with intermediate risk,” Dr. Tward said.
“It took me a while to believe my own data, but we have used this test for several years to help men decide if they would like to have hormone therapy after radiation. Patients clearly benefit from this information,” he said.
The 2.112 cut point for CCR was determined from a prior study that was presented at GUCS 2020 (Abstract 346) and recently accepted for publication.
In the validation study Dr. Tward presented at GUCS 2021, 70% of patients had intermediate-risk disease, and 30% had high- or very-high-risk disease according to National Comprehensive Cancer Network criteria.
All 741 patients received RT equivalent to at least 75.6 Gy at 1.8 Gy per fraction, with 84% getting or exceeding 79.2 Gy. About half the men (53%) had ADT after RT.
Genetic testing was done on stored biopsy samples years after the men were treated. Half of them were below the CCR threshold of 2.112. For those above it, the 10-year risk of metastasis was 25.3%.
CCR outperformed CCP alone, CAPRA alone, and NCCN risk groupings for predicting metastasis risk after RT.
Though this validation study was “successful,” additional research is needed, according to study discussant Richard Valicenti, MD, of the University of California, Davis.
“Widespread acceptance for routine use faces challenges since no biomarker has been prospectively tested or shown to improve long-term outcome,” Dr. Valicenti said. “Clearly, the CCR score may provide highly precise, personalized estimates and justifies testing in tiered and appropriately powered noninferiority studies according to NCCN risk groups. We eagerly await the completion and reporting of such trials so that we have a more personalized approach to treating men with prostate cancer.”
The current study was funded by Myriad Genetics, the company that developed the Prolaris test. Dr. Tward disclosed relationships with Myriad Genetics, Bayer, Blue Earth Diagnostics, Janssen Scientific Affairs, and Merck. Dr. Valicenti has no disclosures.