Authors in the Journal of Clinical Oncology discuss hypotheses on the differences in mutations and implications for treatment with PARP inhibitors.
The year 2020 was a watershed in prostate cancer treatment, with the approval of 2 poly (ADP)-ribose polymerase (PARP) inhibitors—rucaparib and olaparib—for patients with metastatic castration-resistant prostate cancer (mCRPC).
The FDA labels are different, with the olaparib (Lynparza) approval covering patients with a germline or somatic mutation in at least 1 of 14 homologous recombination repair (HRR) genes, including BRCA1 and BRCA2. The rucaparib (Rubraca) approval covers patients with prostate cancer who have germline or somatic BRCA1 or BRCA2 mutations and who have been previously treated with androgen receptor–directed therapy and a taxane-based chemotherapy.
The authors of the JCO commentary write that at long last, the use of PARP inhibitors will make their way into prostate cancer treatment, after their success in breast and ovarian cancer—and many years after genetic counselors guided families on the connections between BRCA1 and BRCA2 presence in breast and ovarian among female family members and prostate cancer among the men.
But the there are some important differences, which the authors, Mark C. Markowski, MD, PhD, and Emmanuel S. Antonarakis, MD, of the Sidney Kimmel Cancer Center at Johns Hopkins Medicine, explore in their commentary. Unlike breast and ovarian cancers, “where the prevalence of the 2 genes is roughly equal,” the number of BRCA1 patients in prostate cancer is quite rare relative to those with BRCA2. The number of patients with BRCA1-altered mCRPC is just 21 patients—so small that it will take many more studies to gain a firm grasp on how well PARP inhibitors work in BRCA1 mutations compared with BRCA2.
The authors discussed studies that appear to show “dampened clinical activity” in patients with prostate cancer driven by BRCA1 vs BRCA2 mutations and discuss 4 possible hypotheses to explain the differences:
(1) Are BRCA1 alterations less often germline lesions than BRCA2 alterations? The authors say this is not likely. They cited several studies but noted the most important was a pan-cancer analysis (Sokol et al) that included more than 7100 prostate cases in which germline mutations affected 35% of the BRCA1 mCRPC cases compared with 50% of the BRCA2 mCRPC cases—so there might be a difference, but it’s not huge.
(2) BRCA1 alterations are less often biallelic mutations than BRCA2 alterations. The authors said this seems to be true. In the same pan-cancer study, 50% of the BRCA1 alterations in prostate cancer were biallelic compared with 90% of the BRCA2 alterations.
(3) Do BRCA1 mutations result in attenuated HRR deficiency compared with BRCA2 mutations? The authors say this is “not likely.” They cite numerous studies that compute deficiency scores, and conclude, “with respect to the BRCA1/2 genes, however, there is no evidence of differential HRR dysfunction when comparing alterations in the 2 genes.”
(4) BRCA1 mutations have more genomic co-alterations, such as TP53 or PTEN, than is the case with BRCA2 mutations. The authors conclude this is likely, especially for TP53, after consulting available studies as well as a publicly available data bank.
“Indeed, the availability of genomically selected therapies for our patients with BRCA1/2- altered advanced prostate cancer represents a welcome addition to our therapeutic armamentarium and is a giant step forward in the management of this disease,” they conclude.
Markowski MC, Antonarakis ES. BRCA1 versus BRCA2 and PARP inhibitor sensitivity in prostate cancer: More different than alike? J Clin Oncol. 2020;38(32):3735-3739. doi: 10.1200/JCO.20.02246