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How I Currently Use PARP Inhibitors to Improve Patient Outcomes in Breast Cancer

Mark E. Robson, MD

Chief, Breast Medicine Service
Attending Physician
Clinical Genetics and Breast Medicine Services
Department of Medicine
Memorial Sloan Kettering Cancer Center
New York, New York

Mark E. Robson, MD has disclosed that he has received consulting fees from Astra Zeneca and Pfizer.

View ClinicalThoughts from this Author

Released: September 22, 2020

Inhibitors of poly ADP ribose polymerase (PARP), a key enzyme in the repair of single-stranded DNA breaks, are now an important treatment option for selected patients with breast cancer. Olaparib is approved by the FDA for patients with HER2-negative metastatic breast cancer (MBC) and deleterious or suspected deleterious germline BRCA mutations who received previous chemotherapy for breast cancer. Similarly, talazoparib is approved by the FDA for patients with HER2-negative, locally advanced breast cancer or MBC and deleterious or suspected deleterious germline BRCA mutations. This commentary discusses key current questions about the optimal use of PARP inhibitors in the treatment of breast cancer.

Now that PARP inhibitors are an established option for breast cancer treatment, which patients should be tested for BRCA mutations, and how should they be tested?

In the last couple of years, there has been an increasing awareness that the traditional factors used to predict the likelihood of BRCA mutations, such as young age and family history, are perhaps not as sensitive and specific as previously thought. In fact, BRCA mutations are often found in nontraditional patient subpopulations, such as older women or women with no family history of breast cancer. This doesn’t necessarily mean that all patients with breast cancer need detailed risk assessment; when it comes to selecting therapeutic options, I think it makes sense to use a broader approach to testing that would identify less common but actionable events such as BRCA mutations. After all, if there’s even a small chance of identifying a helpful therapy, it is worth looking for it. My approach is to test essentially all patients with MBC for BRCA mutations, preferably relatively early in their disease or treatment course.

BRCA mutation testing can be either somatic or germline. In contrast with other malignancies in which PARP inhibitors play a role (eg, ovarian cancer), the indication for PARP inhibition in MBC is limited to those patients with germline BRCA mutations. This means that even if tumor testing identifies a BRCA mutation, it is important to determine if it is germline (inherited) or somatic (acquired) before a PARP inhibitor can be prescribed. In the future, it is possible that the use of PARP inhibitors in patients with breast cancer will be extended to those with somatic BRCA mutations as well.

Another question with regard to germline testing is whether a multigene panel should be used or a test that is specific for just BRCA1 and BRCA2. There are hints that PARP inhibitors may be effective in women who have mutations in genes involved in DNA repair other than BRCA1 and BRCA2. So, while those genetic mutations are not yet part of the indication, it may be worthwhile not only to test a broader population of patients with breast cancer, but also to use a broader test to identify patients who are most likely to benefit.

Which studies inform first-line treatment choice in a BRCA mutation carrier with metastatic triple‑negative breast cancer (TNBC)?

Two issues are important in answering this question. First, previously, clinicians had to determine whether to initially use a PARP inhibitor or a platinum‑containing regimen. There are no direct head‑to‑head comparisons, so any data that speak to that question are essentially cross‑trial comparisons. OlympiAD and EMBRACA were the pivotal phase III trials leading to the single-agent approvals of olaparib and talazoparib, respectively, in BRCA-mutated MBC. In both studies, the ORR and PFS were very similar to the BRCA-mutated cohort receiving carboplatinum in the TNT study of first-line carboplatin vs docetaxel in advanced TNBC. The TNT trial, however, used only a limited course of platinum‑based therapy. The recently published phase III BROCADE3 trial evaluated carboplatin and paclitaxel, with or without the PARP inhibitor veliparib. Results showed not only an improvement in PFS with the addition of veliparib (median: 14.5 months), but also a much higher response rate and improved PFS for carboplatin plus paclitaxel compared with single-agent olaparib and talazoparib in EMBRACA (median PFS: 8.6 months) and OlympiAD (median PFS: 7.0 months). Certainly, for now, a PARP inhibitor is a very reasonable choice for first‑line therapy of metastatic TNBC, although additional studies will be needed to determine whether platinum‑based therapy may be a more durable strategy (either alone or with PARP inhibitor maintenance).

The other question in this setting, of course, is immunotherapy. In the United States, the PD-L1 inhibitor atezolizumab in combination with nab‑paclitaxel is approved to treat patients with metastatic TNBC. Of note, the initial PFS and ORRs are not dramatic, but there is a suggestion of an OS advantage with that regimen in unselected patients with metastatic TNBC. My personal approach is to test for PD-L1 expression in all patients with metastatic TNBC, whether or not they have a BRCA mutation. However, there may be individuals who want to avoid IV chemotherapy and, for them, a PARP inhibitor remains a reasonable choice.

What is the role of PARP inhibition in women with a BRCA mutation and metastatic hormone receptor–positive breast cancer?

In OlympiAD, there was a suggestion that olaparib was less effective in hormone receptor–positive patients than in hormone receptor–negative patients. That was only evident in the primary endpoint of PFS; other endpoints did not show any decreased benefit of olaparib in hormone receptor–positive disease. In the EMBRACA trial of talazoparib there was no difference in OS between hormone receptor–positive and hormone receptor–negative patients. My interpretation of these findings is that PARP inhibitors do work in individuals with hormone receptor–positive breast cancer and, therefore, are a reasonable first‑line option. However, the combination of aromatase inhibitors and CDK4/6 inhibitors is highly effective in this same setting. Unfortunately, because of overlapping myelosuppression, it is not yet clear if combining a PARP inhibitor with a CDK4/6 inhibitor is feasible. Because the PFS and, potentially, OS are so dramatically improved with CDK4/6 inhibitor therapy, my approach in hormone receptor–positive patients with MBC and mutated BRCA is still to use an aromatase inhibitor plus a CDK4/6 inhibitor as first‑line therapy and reserve the PARP inhibitor for second‑line therapy.

Is there a role for PARP inhibition in patients with early breast cancer and a BRCA mutation?

OlympiA (NCT02032823) is an ongoing, large, randomized phase III trial of olaparib vs placebo upon completion of conventional therapy in patients with high‑risk BRCA‑associated early breast cancer. This trial has completed accrual but has not yet reported any data. Until there is some evidence documenting a meaningful benefit to adjuvant PARP inhibitors, I would not utilize this approach, even in a high‑risk setting.

There are some very interesting data emerging from studies by Litton and colleagues for neoadjuvant talazoparib; in relatively small, early trials, it does appear that PARP inhibition in a BRCA mutation carrier can induce pathologic CRs at a relatively high rate. These early studies showed a pCR rate of approximately 50%. However, as yet there are no EFS data, so it does not seem appropriate to replace conventional chemotherapy with a PARP inhibitor in the neoadjuvant setting. I would be very interested to see continued exploration of this as a potential alternative or incremental therapy for BRCA carriers.

Have any new PARP inhibitor–associated toxicities been identified after FDA approval?

It is reassuring that no new PARP inhibitor–associated toxicities have been identified with continued long-term follow up of both the EMBRACA and the OlympiAD trials. Specifically, there has been no evidence of increased treatment‑associated myelodysplasia or acute myelogenous leukemia, although these were significant concerns based on early‑stage trials. The toxicity associated with PARP inhibitors in MBC continues to be largely gastrointestinal plus myelosuppression, with only slight differences between the 2 approved agents.

For olaparib, anemia tends to be quite prominent in some patients and can be severe enough to require transfusion. It is important to monitor hemoglobin levels early in the course of therapy to identify an acute drop if it occurs. For talazoparib, both anemia and thrombocytopenia can be quite significant and, again, careful monitoring early in the course of treatment is important. Of note, the anemia does not appear to be cumulative—in other words, it’s not usually a slow, progressive decline, so if it happens it tends to be sudden.

Gastrointestinal toxicity, in particular nausea and vomiting, can be quite significant with PARP inhibition, particularly at the beginning of therapy. I typically prescribe an oral antiemetic in case patients have problems at home. Fortunately, tachyphylaxis and nausea generally become less of an issue with ongoing therapy.

What are key future directions for PARP inhibitor therapy in breast cancer?

There is great interest in exploring PARP inhibitors as maintenance therapy after platinum‑based induction treatment. This approach has been used for many years in ovarian cancer, but has not been a common treatment paradigm in breast cancer. Using a PARP inhibitor sequentially with platinum‑based therapy helps to both sustain response and minimize the toxicity of the chemotherapy.

Another interesting approach is to combine PARP inhibitors with immunotherapy, specifically checkpoint inhibitors, with the hypothesis that PARP inhibitor therapies could improve responses to immunotherapy. Results from initial single‑arm studies, such as MEDIOLA, have suggested good response rates, with some durable responses, using this approach. A number of larger breast cancer trials are now exploring combinations of PARP inhibitor therapy with checkpoint inhibitors in the neoadjuvant setting and as maintenance therapy after induction.

Another question is whether the benefits of PARP inhibitor therapy in breast cancer can be extended beyond individuals with germline BRCA1 and BRCA2 mutations. We know that these drugs work in ovarian cancer with somatic mutations, and in other diseases, so there’s no obvious reason why they shouldn’t work in patients with breast cancer with somatic BRCA1 and BRCA2 mutations. In fact, results from the recent phase II TBCRC 048 trial showed responses to olaparib in 8 of 16 patients with MBC and somatic mutations in BRCA1 or BRCA2 without germline mutations. Hopefully, we will be able to use this approach in the clinic in the near future.

Some patients with breast cancer who have germline and/or somatic mutations in other genes in the homologous recombination repair pathway may also respond well to PARP inhibition. In TBCRC 048, 8 of 11 participants with germline mutations in PALB2 had a significant response rate to olaparib. Extrapolating this biological rationale, there could also be benefit in patients who have mutations in RAD51C and RAD51B, which are relatively uncommon in breast cancer but nonetheless do significantly affect homologous recombination repair. It is important to note that not all patients with germline mutations are likely to respond to PARP inhibition. For instance, patients with breast cancer associated with mutations in Chk2 or ATM do not appear to benefit from PARP inhibitor therapy.

Looking forward, there is hope that PARP inhibitors will be of benefit even in patients with TNBC and no identified germline or somatic mutations in homologous recombination repair pathway genes, but who nonetheless have homologous recombination deficiency. This may be due to promoter methylation of BRCA1 and RAD51C or through as-yet unknown mechanisms. It would be of great help to identify a phenotypic biomarker of homologous recombination deficiency in tumors, regardless of whether they have a germline or somatic mutation in order to identify patients in this group who might benefit. We need both more sensitive and more specific assays to maximize benefit from PARP inhibitors in breast cancer treatment, and I believe this will be a robust area of investigation over the next few years.

Have you begun using PARP inhibition to treat your patients with breast cancer? Share your experience and concerns in the comment box below!

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