HR Alterations in BRCA Mutations
High-grade serous carcinoma, the most common type of ovarian cancer, often harbors homologous recombination (HR) alterations, most often involving BRCA1 or BRCA2 mutations.
“Given that these tumors are HR-deficient, BRCA -mutated tumors depend on alternative error prone or mutagenic DNA repair pathways,” Dr Konstantinopoulos said.
HR-deficient tumors with BRCA mutations have been found to exhibit a higher mutational load than BRCA wild-type ovarian cancers. However, the overall mutational burden is less than 10 mutations/Mb, “which is where we start to see responses to immune checkpoint blockade by itself,” Dr Konstantinopoulos said.
HR-deficient ovarian cancers with BRCA mutation also exhibit higher neoantigen load compared with HR-proficient ovarian cancers. The overall neoantigen load, however, is 1 log less than tumors with high microsatellite instability and 2 logs less than tumors with POLE mutations.
Ovarian cancers with BRCA mutations also exhibit a high number of tumor-infiltrating lymphocytes (TILs), defined as ≥20 TILs per high-power field, and high PD-L1 expression in immune cells, but not in tumor cells.
These findings indicate that ovarian cancers with BRCA mutations may be more immunogenically “hot” than wild-type tumors. But even in “hot” tumors, single-agent checkpoint inhibitor therapy has induced responses in only 8% to 15% of patients after previous treatment, with higher rates seen in patients with high PD-L1 expression.
Cytotoxicity Effects of PARP Inhibitors
PARP inhibitors exhibit direct cytotoxicity in tumors with BRCA mutations or in HR-deficient tumors, which is exerted mainly by 2 mechanisms. One is inhibition of base excision repair, which leads to double-strand breaks that are highly toxic in an HR-deficient background. The other mechanism is trapping of the PARP-DNA complex, leading to a collapse of the replication fork.
Cytotoxicity is only part of the antitumor activity of PARP inhibitors, Dr Konstantinopoulos said. In a mouse model of BRCA mutation–positive ovarian cancer, olaparib (Lynparza) was shown to activate the stimulator of interferon genes (STING) pathway.
STING pathway inhibitors (ie, type 1 interferon response inhibitors) administered at the same time as olaparib attenuated the response to olaparib, “suggesting that the STING pathway in the type 1 interferon response plays a very important role in the antitumor activity of olaparib,” he said. PARP inhibitor antitumor immunity in ovarian cancer with BRCA mutations could be augmented by PD-1 blockade.
Investigators at M.D. Anderson Cancer Center recently found that PARP inhibitors also elicit STING-dependent antitumor immunity, even in BRCA wild-type or HR-proficient models. In these models, the antitumor activity of the newest PARP inhibitor talazoparib (Talzenna) was also augmented by PD-L1 blockade.
Therefore, the direct cytotoxic effect of PARP inhibitors is dependent on HR deficiency; HR-proficient tumors don’t respond directly. Unlike the direct cytotoxic activity, the antitumor immunity elicited by PARP inhibitors does not seem to be dependent on HR deficiency and may be relevant for HR-proficient tumors.
PARP plus Immune Checkpoint Inhibition
Data from 2 recent trials clinically demonstrate these concepts. One is the MEDIOLA trial, which was a phase 2 basket clinical trial of the combination of olaparib plus durvalumab (Imfinzi).
Results from the 34 patients with germline BRCA mutation–positive, platinum-sensitive relapsed ovarian cancer showed a 19% complete response rate and a 53% partial response rate, for an overall response rate of 72%, which was consistent in patients with 1, 2, or ≥3 previous lines of therapy.
The second study is TOPACIO, a phase 1/2 clinical trial of the combination of niraparib (Zejula) plus pembrolizumab (Keytruda) in patients with mostly BRCA wild-type and platinum-resistant ovarian cancer (enriched for HR proficiency). In the 60 patients who were evaluated for efficacy, the confirmed objective response rate was 18%, with a disease control rate of 65%. Of the 28 patients with stable disease, 9 patients had stable disease for more than 6 months and 2 patients had stable disease for more than 1 year.
Clinical activity was observed across all patient cohorts, regardless of platinum status (resistant, refractory, or ineligible), previous treatment with bevacizumab (Avastin), BRCA mutation status, PD-L1 expression, and HR-deficiency status.
“Results of other combinations of immune checkpoint blockade with inhibitors of the DNA damage response are eagerly awaited,” concluded Dr Konstantinopoulos.