The 22-gene Decipher genomic classifier is a novel technique that in previous trials has demonstrated efficacy in improving prognosis for patients with high risk localized, post-prostatectomy, and metastatic and non-metastatic castration-resistant prostate cancer.
A recent phase 3 trial investigated the Decipher genomic test’s ability to improve prognosis in patients with intermediate-risk prostate cancer.1 In this interview, Daniel E. Spratt, MD, discusses the findings of this study and how they support ongoing personalized therapy in this population of patients. Spratt is a Vincent K. Smith professor and chair at Case Western Reserve University School of Medicine and chair of radiation oncology at University Hospitals Cleveland Medical Center in Cleveland, Ohio.
This study was a secondary analysis, really a translational analysis, of a phase 3 randomized trial [of] NRG Oncology's RTOG 0126. That's a randomized trial of low-dose radiation vs high-dose radiation therapy, both with external beam. There was no hormone therapy allowed for these patients, [who] were predominantly a more favorable intermediate-risk population. That trial was a negative trial. Technically, its primary end point was overall survival, but dose escalation didn't improve some secondary end points, such as biochemical recurrence. The real question that we were after, and what we were asking was, "[Since the] trial was opened in 2001—we're over 20 years later [now]—what about all these new prognostic tools? The Decipher? Or the 22-gene genomic classifier? What if we went back, sampled, and assessed the tissue that was banked from those patients, and see [whether] Decipher [worked]? Did it improve prognostic performance? What's the utility of it in the setting of intermediate risk [in] a big phase 3 trial?
First of all, it's the first time that any gene expression test has been analyzed in a randomized trial, even if it's post-hoc, in intermediate-risk patients. And so, it was interesting because Decipher, similar to some other trials that have been published, was independently prognostic for every single end point. It was prognostic for biochemical recurrence, time to salvage treatment, distant metastasis, metastasis-free survival, death from prostate cancer, and even overall survival. Furthermore, what was somewhat surprising was that although Decipher is known to always be prognostic in the studies, meaning that it can better risk-stratify patients, it also had a signal that it might be predictive. What I mean by that is those with lower Decipher scores derived very minimal benefit from dose escalation with radiation [and] those with higher Decipher scores actually derived a pretty substantial benefit. But the actual relative benefit in metastasis-free survival was significantly greater in those with higher Decipher scores than those with lower. So, putting it all together, what it showed, with very high-quality evidence, [was] that this genomic test is prognostic and probably identifies patients that derive more absolute benefit from dose escalation.
Right now, intermediate-risk prostate cancer [is] one of the most, [what we call], 'heterogeneous disease states.' There [are] some men that we recommend active surveillance to and there [are] some men we recommend multi-modality therapy for. I think what this study is really going to help reinforce is that for men with favorable intermediate-risk disease, especially with a low Decipher score, their risk of long-term metastatic disease is very low. And really, what is the merit or benefit of treatment intensification? I would say it's questionable. Are those the patients we should be considering active surveillance for? I think it reinforces [that] for intermediate-risk patients that have a lower Decipher score, adding hormone therapy, which sometimes people do, probably is not going to improve their long-term outcomes. Similarly, dose intensifying with things like brachytherapy, or further stereotactic body radiation therapy boost is not going to probably improve their outcomes because with just standard dose escalation they have good outcomes. But for patients that happen to have high Decipher scores, there still is a risk of metastatic disease in these patients. And so, I think that this definitely warrants standard of care radiation and hormone therapy for these patients or other forms of radical therapy.
There [are] 2 prospective, large phase 3 trials that are actively enrolling. One is called NRG-GU009 [(NCT04513717)],2 and [the other] one is NRG-GU010 [(NCT05050084)].3 These are both very large, over 2000-person, phase 3 trials. The [NGR-GU010] trial is specifically an unfavorable intermediate risk disease, and based specifically on the Decipher score, patients will either be randomized to get radiation alone with or without hormone therapy. So, it's trying to actually find patients that we can omit hormones together with the radiation, or it's going to take the higher Decipher patients and say, "Should we intensify their treatment by adding further hormone blockade with darolutamide [Nubeqa]?"
Now, there are at least 7 and counting phase 3 trials that have reported results, looking at the Decipher genomic test. And so, I think that it's very clear that this test is independently prognostic. So, it improves risk stratification, and I think for the practicing urologist, especially when there [are] these decisions to be made about a favorable intermediate—should you do surveillance? Should you treat them?—I think this test is saying that clearly those with higher genomic risk scores have a fairly unfavorable outcome, and probably should be screened out of those surveillance populations. A lot [of] further work is ongoing [to] help us better understand the exact patients to use these tests on.
It's a very exciting time. We are, some would say, many decades behind breast cancer, which has been using gene expression tests for almost 20 years. Now, we have, as I said, [data from] 7 and counting phase 3 trials that [have] been looked at, and multiple more ongoing. And so, I think this is a great option for patients and practitioners to personalize therapy. It should be part of radiation oncologists’, urologists’, [and] medical oncologists’ training, continued reading, and learning, to make sure you provide the option to patients. Not every patient needs one of these tests. There are costs, but [it is important], for patients that it may help improve the risk stratification [of] and potentially change their management, to really make sure you're providing this [option].
1. Spratt DE, Huang HC, Michalski JM, et al. Validation of the performance of the Decipher biopsy genomic classifier in intermediate-risk prostate cancer on the phase III randomized trial NRG Oncology/RTOG 0126. Paper presented at: 2022 ASCO Genitourinary Cancers Symposium; February 17-19, 2022; San Francisco, California. Abstract #269
2. Two studies for patients with high risk prostate cancer testing less intense treatment for patients with a low gene risk score and testing a more intense treatment for patients with a high gene risk score, The PREDICT-RT trial). ClinicalTrials.gov. Updated February 3, 2022. Accessed February 16, 2022. https://clinicaltrials.gov/ct2/show/NCT04513717
3. Two studies for patients with unfavorable intermediate risk prostate cancer testing less intense treatment for patients with a low gene risk score and testing a more intense treatment for patients with a higher gene risk score. ClinicalTrials.gov. Updated January 24, 2022. Accessed February 16, 2022. https://clinicaltrials.gov/ct2/show/NCT04513717