High-Risk Prostate Cancer: Implications of Entering a More Molecular, More Genomic Era
Molecular and genomic tests have the potential to add key prognostic data to the assessment of earlier-stage prostate cancer. Ongoing trials seek to validate the use of genomic risk stratification as a means of selecting patients for tailored therapeutic interventions.
How is the approach to high-risk, locally advanced disease evolving to incorporate genomics and molecular testing?
Associate Professor, Department of Medical Oncology & Therapeutics Research
“Studies such as these indicate that we will very likely be seeing the utilization of these genomic classifiers in clinical decision making in the future.”
It is very exciting to see genomic prognosticators such as the Decipher test (Veracyte, Inc) moving into clinical trials for prospective testing. Whether that information can be used to refine the treatment plan (ie, so that we are not treating all patients with high-risk prostate cancer in the same way) is very interesting. Molecular prognosticators have great potential to complement traditional clinical variables that may be less precise or more subjective.
NRG Oncology has several trials using the Decipher risk score to assign patients to therapeutic intensification or deintensification based on high or low Decipher scores, respectively. These types of prospective studies are very important, and we look forward to having access to treatment strategies that can be assigned based on the genomic risk stratification.
Another example of work being done in this area is the phase 3 ERADICATE study of early intervention after radical prostatectomy with androgen deprivation therapy (ADT) plus darolutamide in men who are at the highest risk of prostate cancer metastasis. In that study, patients with high risk by clinical features (CAPRA-S scores of ≥3) after radical prostatectomy undergo Decipher testing, and eligible individuals with high-risk Decipher scores (>0.6) are then randomized to treatment with ADT with darolutamide or placebo for 12 months. Studies such as these indicate that we will very likely be seeing the utilization of these genomic classifiers in clinical decision making in the future.
High-risk localized prostate cancer is also one of the settings in which prostate-specific membrane antigen positron emission tomography (PSMA PET) has been shown to potentially be very helpful. For instance, if certain pelvic lymph nodes are avid on a patient's PSMA PET scan, then it makes sense to target those lymph nodes as part of the definitive treatment, regardless of whether surgery or radiation is planned. This is something that still requires prospective validation; however, it is a clinically sensible approach. More prospective trials are also needed to understand how best to respond to other types of findings, such as extrapelvic disease. But I think that, increasingly, clinicians will be obtaining PSMA PET scans in these higher-risk patients.
Director, CPI, Carolina Urologic Research Center
“Molecular and genomic profiling can be absolutely key to informing patients about their risk so that we can make the best-possible decisions about the next steps.”
This has been a very positive advancement that has developed over time. Historically, we staged patients who had unremarkable findings on conventional imaging as high risk based on their subjective digital rectal examinations, absolute prostate-specific antigen values, and Gleason score histopathologies.
Over the course of time, molecular profiling has become available, with different assays emerging (eg, the Prolaris test [Myriad Genetics, Inc], the Oncotype DX Genomic Prostate Score [Exact Sciences Corporation], and the Decipher Prostate Genomic Classifier Scores). These essentially take the histopathologic slides with tissue and then help stratify the risk of aggressiveness, in addition to the digital rectal examination, prostate-specific antigen, and histopathology. We recognize that there is heterogeneity within the traditionally defined categories. That is, a patient who may appear to be favorable intermediate or unfavorable intermediate (grade groups 2 and 3, respectively) may actually have more aggressive disease or less aggressive disease. Alternatively, genomic testing may be confirmatory, yielding a consistent picture of intermediate-grade disease.
This type of profiling clearly helps to inform the shared treatment decision-making process with patients, which can be quite challenging. We also consider factors such as the patient’s age, comorbidities, voiding, and sexual function. Options for an individual might include continued surveillance, radiation, radiation with systemic ADT, prostatectomy, or, perhaps, participation in clinical trials that are investigating adjuvant strategies. Molecular and genomic profiling can be absolutely key to informing patients about their risk so that we can make the best-possible decisions about the next steps.
Section Head, Medical Oncology
“ . . . it may be possible to identify those with the highest risk of prostate cancer metastasis by genomic stratification after radical prostatectomy and to improve their outcomes with adjuvant therapy, but this remains to be seen.”
My urologic colleagues have been integrating a variety of genomic risk assessment tools based on tissue testing into clinical practice over the past decade to help inform management decisions for clinically localized disease. One example of their clinical utility is in the consideration of whether active surveillance would be appropriate in a patient with intermediate-risk disease (eg, low-volume Gleason 3+4 disease).
Although we have made a good start with these tests, we still have a way to go. We need prospectively validated genomic risk calculators and scores for prostate cancer. In breast cancer, prospectively validated genomic risk scores have been available and have been widely integrated into clinical practice for some time.
Another challenge with genomic testing for clinically localized prostate cancer is that none of the tests have been compared in a meaningful way. It is not clear to me that one of these tests is better than the others. The cooperative group study that was mentioned by Dr Dorff represents efforts to try to prospectively validate what is being done in the clinic. Thus, it may be possible to identify those with the highest risk of prostate cancer metastasis by genomic stratification after radical prostatectomy and to improve their outcomes with adjuvant therapy, but this remains to be seen.
ClinicalTrials.gov. 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. Updated April 26, 2022. Accessed August 2, 2022. https://clinicaltrials.gov/ct2/show/NCT05050084
Ebell MH. Prolaris test for prostate cancer risk assessment. Am Fam Physician. 2019;100(5):311-312.
Feng FY, Huang H-C, Spratt DE, et al. Validation of a 22-gene genomic classifier in patients with recurrent prostate cancer: an ancillary study of the NRG/RTOG 9601 randomized clinical trial [published correction appears in JAMA Oncol. 2021;7(4):639]. JAMA Oncol. 2021;7(4):544-552. doi:10.1001/jamaoncol.2020.7671
Hernández CH, Kim Lee D, Sanchez Pérez M, Escobar SH. Accuracy of CAPRA-S score for predicting long-term biochemical progression after radical prostatectomy. Clin Genitourin Cancer. 2019;17(3):e645-e649. doi:10.1016/j.clgc.2019.03.014
Jairath NK, Dal Pra A, Vince R Jr, et al. A systematic review of the evidence for the Decipher genomic classifier in prostate cancer. Eur Urol. 2021;79(3):374-383. doi:10.1016/j.eururo.2020.11.021
Knezevic D, Goddard AD, Natraj N, et al. Analytical validation of the Oncotype DX prostate cancer assay—a clinical RT-PCR assay optimized for prostate needle biopsies. BMC Genomics. 2013;14:690. doi:10.1186/1471-2164-14-690
Morgans AK, Chen Y-H, Ferrari AC, et al. A phase III double blinded study of early intervention after radical prostatectomy with androgen deprivation therapy with darolutamide versus placebo in men at highest risk of prostate cancer metastasis by genomic stratification (ERADICATE). J Clin Oncol. 2022;40(suppl 16):TPS5114. doi:10.1200/JCO.2022.40.16_suppl.TPS5114
NRG Oncology. Accessed August 2, 2022. https://www.nrgoncology.org
Serrano NA, Anscher MS. Favorable vs unfavorable intermediate-risk prostate cancer: a review of the new classification system and its impact on treatment recommendations. Oncology (Williston Park). 2016;30(3):229-236.
Van den Broeck T, Moris L, Gevaert T, et al. Validation of the Decipher test for predicting distant metastatic recurrence in men with high-risk nonmetastatic prostate cancer 10 years after surgery. Eur Urol Oncol. 2019;2(5):589-596. doi:10.1016/j.euo.2018.12.007