Why is rucaparib response higher in BRCA2- versus BRCA1-mutated prostate cancer?

The diminished clinical activity of rucaparib (Rubraca) and other PARP inhibitors in patients with prostate cancer with BRCA1 versus BRCA2 mutations may be explained by zygosity status and additional genomic coalterations, according to an editorial published in the Journal of Clinical Oncology.¹

In the editorial, coauthors Mark C. Markowski, MD, PhD, and Emmanuel S. Antonarakis, MD, both from Johns Hopkins University School of Medicine, explained that the variance in sensitivity to PARP inhibition between BRCA1- and BRCA2-mutated tumors appears to be consistent across this class of agents. They compiled a pooled analysis of PARP inhibitors across several trials (olaparib [Lynparza]: TOPARP-A, TOPARP-B, and PROfound; rucaparib: TRITON2; and talazoparib [Talzenna]: TALAPRO-11) showing that the objective response rate (ORR) was 26.3% (5/19) in BRCA1-positive patients compared with 50% (79/158) in BRCA2-positive patients.

In their editorial, Markowski and Antonarakis provided a deeper dive into the TRITON2 data. The open-label, multicenter, international TRITON2 study, which led to the FDA approval of rucaparib in BRCA-positive metastatic castration-resistant prostate cancer (mCRPC), enrolled male patients with mCRPC associated with 1 of 13 homologous recombination repair gene alterations. Patients had disease progression on androgen receptor–directed therapy and 1 prior taxane-based chemotherapy.

In the study, the PARP inhibitor induced a confirmed ORR per independent review of 43.5% in heavily pretreated patients with mCRPC and a deleterious BRCA alteration.² The ORR was 45.3% in patients with BRCA2 mutations compared with 33.3% in patients with BRCA1 mutations. Further, the PSA response rate was 59.8% versus 15.4%, respectively.

The authors generated several potential hypotheses explaining the variation in response, and considered 2 to have the most potential. The first hypothesis was that BRCA1 alterations are less commonly biallelic mutations compared to BRCA2 alterations. In TRITON2, biallelic mutations were associated with a higher PSA response rate versus monoallelic mutations, at 75% versus 11%, respectively. Among patients in TRITON2 evaluable for zygosity status, only 40% (2/5) of patients with BRCA1 mutations had biallelic alterations, as compared with 85% (34/40) of BRCA2 mutations. The authors wrote that other recent research yielded similar findings.

The second hypothesis Markowski and Antonarakis determined to be likely was that tumors with BRCA1 mutations are more likely than BRCA2-mutated tumors to have additional genomic coalterations, such as TP53 or PTEN, associated with a poor prognosis. Having such mutations could lead to these patients showing a reduced sensitivity to PARP inhibitors. Along this line, it was shown in TRITON2 that coalterations in TP53 and PTEN were more common in patients with BRCA1 versus BRCA2 mutations at 62% versus 42% and 69% versus 29%, respectively. The researchers corroborated these findings using data from the cBioPortal for Cancer Genomics.

In their concluding remarks, Markowski and Antonarakis urged caution when extrapolating their findings to the population at large.

“Ultimately, because of the relative rarity of both germline and somatic BRCA1 mutations compared with BRCA2 mutations in prostate cancer (unlike the situation in breast or ovarian cancers, where the prevalence of two genes is roughly equal), our conclusions related to PARP inhibitor sensitivity should be interpreted with caution,” the authors wrote.

“Additional studies and meta-analyses will be required to gain clearer insights on the potential differential efficacy of PARP inhibitors in prostate cancers with BRCA1 versus BRCA2 mutations and to understand the biologic mechanisms underpinning this phenomenon. At this time, both rucaparib and olaparib are indicated, and should be considered, for the treatment of mCRPC patients with either BRCA1 or BRCA2 mutations,” added Markowski and Antonarakis.

References

1. Markowski MC, Antonarakis ES. BRCA1 versus BRCA2 and PARP inhibitor sensitivity in prostate cancer: more different than alike? [published online September 1, 2020]. Editorial J Clin Oncol. doi: 10.1200/JCO.20.02246

2. Abida W, Patnaik A, Campbell D, et al. Rucaparib in men with metastatic castration-resistant prostate cancer harboring a BRCA1 or BRCA2 gene alteration [published online August 14, 2020]. J Clin Oncol. doi: 10.1200/JCO.20.01035