Excitement Grows About PARP Inhibitors in BRCA-Mutated TNBC

Joyce A. O’Shaughnessy, MD

Expanded Role of BRCA1/2 Testing

Approximately 15% to 20% of breast cancers are of the triple-negative phenotype, testing negative for estrogen receptors (ERs), progesterone receptors, and HER2.¹ Historically, triple-negative breast cancer (TNBC) tumors have been associated with an aggressive and early pattern of metastases and a lack of therapeutic targets compared with endocrine-sensitive tumors. TNBC tumors include many subgroups with distinct molecular characteristics and biomarkers, paving the way for improved targeted treatments in the near future. With the recent FDA approval of the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib, patients with TNBC and deleterious germline BRCA mutations now have a targeted treatment.² During an OncLive Peer Exchange^® moderated by Joyce A. O’Shaughnessy, MD, a panel of experts discussed the role of BRCA1/2 mutation testing and how and when to incorporate PARP inhibitors into the care of patients with BRCA-positive TNBC. They also discussed the potential for combining PARP inhibitors with other agents.A strong association has been shown between TNBC and BRCA mutations, particularly with respect to the BRCA1 gene. The proportion of BRCA1 mutations among triple-negative cases has been reported to range from 7% to 28%, whereas the proportion of BRCA2 mutations ranges from 1% to 17%.³ In patients with TNBC, the National Comprehensive Cancer Network (NCCN) recommends genetic risk evaluation in those diagnosed at ≤60 years.³ With the approval of olaparib, the NCCN expanded its BRCA1/2 testing recommendations to include patients with recurrent or metastatic HER2-negative disease eligible for single-agent therapy.⁴

“We no longer have to restrict [BRCA1/2 testing] to the early stage, as it now makes sense in the metastatic HER2-negative setting because we have a novel therapeutic available,“ said O’Shaughnessy. The other panelists concurred. “I think it’s very reasonable to test anyone with metastatic TNBC for BRCA,” said Aditya Bardia, MD, MPH. “Even if I identify [only a handful of] patients who otherwise would not have been identified based on the classic family history associated with BRCA carriers, I would be happy.”

PARP Inhibitor Therapy for TNBC

However, to ensure proper identification of such patients, clinicians might need to readdress genetic counseling conversations. “There’s a pool of patients to whom we may have mentioned genetic counseling who didn’t pursue that, and now this has treatment implications and is not just risk assessment,“ said Tiffany Traina, MD. “We need to make sure we’re not missing potential candidates for [PARP inhibitor] therapy.”In January 2018, olaparib (Lynparza) became the first FDA-approved treatment for patients with germline BRCA-mutated, HER2-negative metastatic breast cancer.² It is indicated for those previously treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting. Approval was based on data from the OlympiAD study (NCT02000622), which randomly assigned patients 2:1 to olaparib 300 mg orally twice daily or physician’s choice of chemotherapy (capecitabine, vinorelbine, or eribulin).⁵ “There was a significant improvement in progression-free survival [PFS] on the order of about 3 months [7.0 months for olaparib versus 4.2 months for chemotherapy],“ said Claudine Isaacs, MD, noting the objective response rate (ORR) was about 60%.

Another PARP inhibitor that is expected to be approved soon for patients with germline BRCA1/2 mutations is talazoparib (BMN 673), which is being assessed in the EMBRACA trial (NCT01945775).⁶ “Again, there was about a 3-month prolongation in PFS, so very similar findings favoring the use of a very targeted therapy in this group of patients,“ said Isaacs. In the study, the median PFS was 8.6 months for those receiving talazoparib and 5.6 months for those receiving physician’s choice of chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine). The ORR was 62.6%, which is comparable to that observed with olaparib in OlympiAD.

Platinum Versus PARP Inhibitors in Sequencing

Although OlympiAD and EMBRACA showed similar results, the panelists noted some differences between these agents. “Talazoparib is more potent than olaparib, and it also has PARP trapping,“ said Bardia. “Talazoparib has slightly more hematological toxicity and that could be because it’s more potent, but we need to be cautious when comparing 2 different trials.”Platinum compounds, including cisplatin and carboplatin, are widely used in the first-line treatment of TNBC. In previously untreated patients, mean response rates (RRs) of 50% and 32%, respectively, have been reported for these agents.7 In previously treated patients, RR declines markedly to less than 10%,⁷ leaving unanswered the question of where PARP inhibitors fit in the treatment scheme.

“When we compare single-agent platinum data, such as from the Isakoff trial, with PARP inhibitor data, the RR is very similar,“ said O’Shaughnessy. “PFS is about the same, but it’s much less toxic to get a PARP inhibitor, so it seems very reasonable to use it early on if you know you’ve got a germline BRCA patient,“ she noted. In the Isakoff trial, the RR in patients with germline BRCA1/2 mutations who were treated with cisplatin or carboplatin reached 54.5%. The median PFS was 2.9 months but reached 3.3 months in mutation carriers.8 All patients had metastatic TNBC; received ≤1 prior cytotoxic chemotherapy for metastatic disease, with no prior cisplatin or carboplatin therapy; and had no active brain metastases.⁸

“If I have a patient with a bona fide germline BRCA mutation, I would feel comfortable using it as a first-line or definitely as a second-line agent, particularly for TNBC,“ said Bardia. He noted that the decision is more difficult in the ER-positive metastatic breast cancer setting because CDK4/6 inhibitors come into play. “Given the data we have with CDK4/6 inhibitors and because there should not be any cross resistance between a CDK4/6 and PARP [inhibitors], in an ER-positive setting I would probably use a CDK4/6 as first-line and consider [a] PARP [inhibitor] as second-line or third-line.”

Brain Metastases

Traina noted that although the data appear to favor using PARP inhibitors early on in patients with metastatic TNBC and deleterious germline BRCA mutations, consideration of previous platinum exposure also is essential to prevent use of PARP inhibitors in cohorts different from those assessed in clinical trials, which could lead to disappointing results. “I think that an important distinction to be aware of is that patients who were eligible for OlympiAD and EMBRACA may have had prior platinum exposure, but they could not progress on a platinum in the metastatic setting, and they may have received their platinum in the adjuvant or neoadjuvant setting,“ she said. “But anywhere between 6 months to 1 year needed to elapse before coming onto a PARP inhibitor. Keeping that in mind will help set expectations,“ she said.Although many breast cancer trials do not include patients with active brain metastases, such as the Isakoff trial, the EMBRACA trial did admit such patients. “I think about 15% of patients on that trial had prior brain metastases,“ Traina said. “That’s a very important subset, as brain metastases are not uncommon,“ noted O’Shaughnessy.

Combination Therapies

EMBRACA trial findings indicate that patients with brain metastases derive the same benefit from talazoparib as those without brain metastases, with the hazard ratio favoring talazoparib over physician’s choice of chemotherapy. “Of course, we’re going to need some more data looking specifically at that issue, but once talazoparib becomes available, we might really consider it for the patient with brain metastases,“ said O’Shaughnessy.As single agents, PARP inhibitors selectively target tumor cells with BRCA1 or BRCA2 tumor suppressor gene mutations and prevent PARP-mediated DNA repair, upon which tumors defective in homologous recombination mechanisms rely on for survival.⁹ These agents may also increase tumor sensitivity to DNA-damaging agents.⁹ Subsequently, there is a great deal of interest in combining PARP inhibitors with other therapeutic agents to amplify tumor killing; however, thus far, not all combinations are proving beneficial.

In the Brightness study, adding the PARP inhibitor veliparib to neoadjuvant carboplatin and paclitaxel and following it with doxorubicin plus cyclophosphamide did not increase the pathologic complete RR.¹⁰ “I don’t know if that means that the platinum alone is contributing so much that we don’t see an incremental advantage there to the PARP inhibitor,“ said Traina. Nevertheless, she warned of the increased toxicity when combining PARP inhibition with other platinum-based agents. “In the metastatic setting, it’s actually been quite challenging to overlap drugs like olaparib with cisplatin or even carboplatin,“ she said.

In contrast, one combination that is showing promise is PARP inhibitors with checkpoint inhibitors.¹¹ “PARP inhibitors affect the repair of DNA, which leads to some genomic instability and more expression of the antigens, which can potentially increase immunotherapy response,“ explained Bardia. He noted that evidence from preclinical models in ovarian cancer suggest that PARP inhibitors may increase PD-1 expression. “So, if you use PARP inhibitors and the PD-1 expression is increased when you add a PD-1 inhibitor, that could potentially lead to synergy,“ he said.

An open-label, phase II basket study of olaparib and durvalumab (Imfinzi), an anti— PD-L1 agent, showed the 2 drugs can be safely combined with good efficacy in pretreated patients with germline BRCA-mutated, HER2- negative metastatic breast cancer.¹¹ “The incidence of severe immunotherapy complications was very low and the toxicities were not overlapping,“ said Bardia, noting that complete and partial responses were observed and that the disease control rate was 80% at 12 weeks. “[The trial] met its primary objective and demonstrated that you could potentially combine these agents, so I think we will likely see more trials combining PD-1 inhibitors with PARP inhibitors,“ he said.

References

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