APCCC 2022: How Can Treatment Be Individualized By Using Genomic Classifiers?

(UroToday.com) The 2022 Advanced Prostate Cancer Consensus Conference (APCCC) Hybrid Meeting included a session on biochemical recurrence, and a presentation by Dr. Felix Feng discussing how treatment can be individualized by using genomic classifiers. Dr. Feng started by highlighting that genomic biomarkers are included in certain treatment guidelines for the management of PSA recurrences. In the NCCN guidelines, the Decipher molecular assay is recommended for risk stratification among men with PSA persistence or recurrence.

Dr. Feng and colleagues have previously validated Decipher in the post-prostatectomy setting. In their systematic review,¹ they included five studies, with 975 total patients, of which 855 patients had individual patient-level data. Of the total cohort, 60.9%, 22.6%, and 16.5% of patients were classified by Decipher as low, intermediate, and high risk, respectively. Over a median follow-up of 8 years, the 10-year cumulative incidence metastases rates were 5.5%, 15.0%, and 26.7% (p < 0.001), respectively, for the three risk classifications:

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Importantly, the results were consistent across multiple subgroups. So, what treatment decisions can be guided using genomic classifiers?

Adding ADT to salvage radiotherapy?
Adjuvant versus salvage radiotherapy?
Assigning a salvage radiotherapy dose?

With regards to adding ADT to salvage radiotherapy, the RTOG 9601 trial² was a phase III randomized clinical trial assessing bicalutamide monotherapy among salvage EBRT patients randomized to bicalutamide 150 mg PO daily vs placebo for 24 months. The overall survival rates at 12 years were 76.3% for patients taking bicalutamide compared to 71.3% taking placebo (p=0.04). Prostate cancer survival rates at 12 years were 5.8% for bicalutamide compared to 13.4% for placebo (p<0.001). Published in 2021 in JAMA Oncology,³ Dr. Feng and his team validated the Decipher genomic classifier in patients with recurrent prostate cancer using data from the RTOG 9601 randomized clinical trial. On multivariable analysis, the genomic classifier was independently associated with distant metastasis (HR 1.17, 95% CI 1.05-1.32; p = 0.006), prostate cancer specific mortality (HR 1.39, 95% CI, 1.20-1.63; p < 0.001), and overall survival (HR 1.17, 95% CI 1.06-1.29; p = 0.002) after adjusting for age, race/ethnicity, Gleason score, T stage, margin status, entry PSA, and treatment arm:

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Importantly, the absolute benefit from hormone therapy is smaller among the low Decipher risk group for the (i) entire cohort and (ii) early salvage radiotherapy (PSA < 0.7 ng/mL).

With regards to adjuvant versus salvage radiotherapy, Decipher may identify patients who benefit from adjuvant radiotherapy. Den and colleagues⁴ examined 188 patients with pT3 prostate cancer or with positive surgical margins at the time of radical prostatectomy who received post-operative radiotherapy. In patients with a low genomic classifier score, there was no difference in rates of metastasis between patients who received adjuvant and salvage radiotherapy. However, in patients with higher genomic classifier scores, patients who received adjuvant radiotherapy had significantly lower rates of metastasis compared to those who were treated with salvage radiotherapy:

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With regards to using Decipher to assess the optimal salvage radiotherapy dose, Dr. Feng discussed the SAKK 09/10 trial,⁵ for which genomic classification was a pre-specified endpoint. This was a multicenter, randomized phase 3 trial performed in 24 centers in Switzerland, Germany, and Belgium. Patients with biochemical progression (PSA >0.1 to 2 ng/mL at randomization) were randomized to 64 Gy versus 70 Gy to the prostate bed; no ADT or pelvic nodal radiotherapy was used. There was no difference in failure from biochemical progression between the two groups after six years of follow-up. Central review of the pathology was associated with a high rate of passing quality control (>97%), and 226 of 350 patients had genomic classifier data for analysis. Additionally, the exploratory analysis on the genomic classifier and pre-salvage PSA with regards to freedom from biochemical progression showed important outcome differentiation when stratified by PSA <= vs > 0.5 ng/mL at randomization:

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So, what treatment decisions can be guided using genomic classifiers?

Adding ADT to salvage radiotherapy? Yes
Adjuvant versus salvage radiotherapy? Maybe
Assigning a salvage radiotherapy dose? Not currently

Dr. Feng concluded his presentation by discussing the individualization of treatment using genomic classifiers with the following take-home messages:

Genomic classifiers can be used to help individualize treatment decisions in the post-prostatectomy PSA recurrent setting
The strongest evidence for a genomic classifier is the use of a Decipher test to identify which patients should not receive ADT with salvage radiotherapy for a PSA recurrence
Additional evidence needs to be generated to support other potential treatment decisions in the PSA recurrent setting

Presented By: Felix Feng, MD, Helen Diller Family Comprehensive Cancer Center, University of California – San Francisco, San Francisco, CA

Written By: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2022 Advanced Prostate Cancer Consensus Conference (APCCC) Annual Hybrid Meeting, Lugano, Switzerland, Thurs, Apr 28 – Sat, Apr 30, 2022.

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