It has been known for at least two decades that germline alterations in BRCA genes are associated with an increased risk of prostate cancer. Dr. Efstathiou traced the path from this initial discovery in 1997, to the published molecular characterization of metastatic castration-resistant prostate cancer (mCRPC) and TOPARP-A trial in 2015, further analysis of the prevalence of DDR mutations in prostate cancer in 2016, to multiple trials looking at the utility of PARP inhibitors in DDR-altered prostate cancers and the subsequent approval of olaparib and rucaparib. Despite recent progress, much more remains to be learned about the optimal management of patients with DDR alterations.
In LBA22, the authors presented a prospective screening study of patients in Israel utilizing PSA and MRI screening in men aged 40-70 with germline BRCA1 (founder 185delAG alteration) or BRCA2 mutations. The authors propose that utilizing a PSA-triage then MRI screening approach may be a useful screening protocol, but Dr. Efstathiou argues that perhaps the number of prostate cancers that would be missed with this approach is too high. Further work to determine the sensitivity of such an approach, balanced with the risk of prostate biopsy, will help elucidate an appropriate strategy.
In 612MO, the authors of the PROREPAIR-A study confirmed the poorer prognosis of patients with germline BRCA2 alterations and prostate cancer, and also examined the co-occurrence of germline BRCA2 alteration with other somatic alterations. They observed that tumors in patients with germline BRCA2 alteration were more likely to have other poor-prognosis genomic features such as MYC amplification and somatic BRCA2 and RB1 co-deletion.
In 614MO, the authors retrospectively examined the impact of DDR mutations on the efficacy of cabazitaxel chemotherapy. A prospective study last year suggested that patients with germline BRCA2 alterations and advanced prostate cancer may not respond as well to docetaxel therapy1 relative to anti-androgens such as enzalutamide. In contrast, this retrospective study suggested that regardless of DDR-mutation status, patients responded comparably to cabazitaxel with regards to PSA decline and radiographic progression-free survival. There was a suggestion of improved overall survival in the DDR-altered cohort, but this may be less related to cabazitaxel and more to the age of the patients (younger) or subsequent treatment and clinical benefit with PARP inhibitor or platinum therapy.
Together, these abstracts cover a range of clinical associations surrounding DDR mutations in prostate cancer. They suggest that MRI-based screening protocols can identify patients who are likely to have clinically significant prostate cancers on biopsy, that co-occurrence of somatic alterations such as MYC amplification are more likely in germline BRCA2 altered patients, and cabazitaxel seems efficacious in patients whose tumors have DDR alterations, which may be in contrast to docetaxel therapy. Further work in all three areas will refine our understanding of DDR alterations in prostate cancer and hopefully optimize the clinical management of this molecular subset of prostate cancers.
Presented by: Eleni Efstathiou, MD, Ph.D., Associate Professor in the Department of Genitourinary Medical Oncology at the MD Anderson Cancer Center, Houston, TX, USA
Written by: Alok Tewari, MD, PhD, Medical Oncologist at the Dana-Farber Cancer Institute, at the 2020 European Society for Medical Oncology Virtual Congress (#ESMO20), September 19th-September 21st, 2020.
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Related Content:
ESMO Virtual Congress 2020: Imaging Based Prostate Cancer Screening Among BRCA Mutation Carriers – Results from the First Round of Screening
ESMO Virtual Congress 2020: Clinical Impact of Somatic Alterations in Prostate Cancer Patients with and Without Previously Known Germline BRCA1/2 Mutations: Results from PROREPAIR-A Study
ESMO Virtual Congress 2020: Cabazitaxel Activity in Men with Metastatic Castration Resistant Prostate Cancer with and without DNA Damage Repair (DDR) Defects