The 2023 American Society of Clinical Oncology (ASCO) annual meeting held in Chicago, IL between June 2nd and June 6th was host to a prostate, testicular, and penile cancers poster session. Dr. Anis Hamid presented the results of an ancillary analysis of CHAARTED, evaluating the landscape and impact of germline pathogenic variants in metastatic hormone sensitive prostate cancer (mHSPC).
Enrichment of germline pathogenic variants in metastatic castration resistant prostate cancer (mCRPC), compared to localized disease, has directly informed genetic testing guidelines. The prevalence and prognostic/predictive associations of such variants are not as well characterized in the mHSPC state, in particular with respect to the effect of susceptibility mutations in DNA damage and repair (DDR) pathways.
In this analysis, the investigators performed whole exome sequencing of germline DNA derived from whole blood available from patients in the phase III CHAARTED trial (NCT00309985) of androgen deprivation therapy (ADT) versus ADT plus docetaxel.
After filtering for low coverage, variant annotation and effect prediction, pathogenic variants from a curated list of 588 prostate cancer-associated genes were reviewed. The prognostic values of the pathogenic variants were evaluated within each treatment arm. The time-to-event outcomes of interest were time to castrate-resistance, time to clinical progression, and overall survival, estimated using Kaplan-Meier curves. The associations between the pathogenic variants and the outcomes of interest were evaluated within each arm using Cox proportional hazards regression models, adjusted for metastatic timing and disease volume.
Of 137 patients, 135 had unique germline exomes that passed downstream analysis. The majority of patients had synchronous (67%) and high-volume (62%) disease. Consistent with results from the overall cohort analysis, this biomarker cohort confirmed the benefit to docetaxel addition in this setting, both with respect to time to CRPC (HR: 0.55, 95% CI: 0.37 – 0.82) and OS (HR: 0.68, 95% CI: 0.44 – 1.07). In total, 61 pathogenic variants were detected, with 49 patients (36.3%) harboring ≥1 pathogenic variant in 41 different genes.
The most frequently mutated gene was BRCA2 (6.7%). In addition, pathogenic variants were found in DDR-associated genes including PALB2 (1.5%), CHEK2 (1.5%), BRCA1 (0.7%) and PMS2 (0.7%) for an overall prevalence of 11.1% (15/135).
Patients with BRCA2 mutations receiving ADT alone had shorter time-to-castrate resistance compared with men without the pathogenic variants, on multivariable analysis (HR: 2.59, 95% CI: 0.91 – 7.39, p=0.074). There was no evidence of a difference in the combination ADT + docetaxel arm (univariable HR: 1.00, 95% CI: 0.31 – 3.25, log rank p=0.1). Metastatic volume and timing were not significantly associated with the presence of germline BRCA1/2 or DDR pathogenic variants.
Dr. Hamid concluded that the prevalence of germline BRCA1/2 and DDR pathogenic variants in mHSPC patients is similar to those with mCRPC. The presence of BRCA2 germline mutations may confer worse outcomes on ADT alone. This supports the need for genetic testing at the time of mHSPC diagnosis.
Presented by: Anis Hamid, MBBS, GU Oncology Research Fellow, Department of Medical Oncology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, Victoria, Australia
Written by: Rashid Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, June 2 – Tues, June 6, 2023.
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