Neil Iyengar, MD

Treating Patients With Germline BRCA-Mutated, HER2-Negative Metastatic Breast Cancer

Question

What are your thoughts about the use of poly([ADP]–ribose) polymerase (PARP) inhibitors in the adjuvant setting in BRCA-mutated, HER2-negative disease?

Answer

The need for new treatment strategies in triple-negative breast cancer and the recent US Food and Drug Administration approvals of PARP inhibitors for the treatment of metastatic, HER2-negative breast cancer in patients with germline BRCA1/2 mutations have fueled interest in testing PARP inhibition for the treatment of early-stage breast cancer. This approach may be of particular interest in patients with high-risk disease (eg, residual disease). Findings from the CREATE-X trial (UMIN Clinical Trials Registry number, UMIN000000843),¹ which demonstrate improved overall survival with extended chemotherapy (capecitabine) in patients with residual disease after definitive therapy, support the development of additional treatment strategies for high-risk early-stage disease.

The OlympiA trial (ClinicalTrials.gov Identifier: NCT02032823) is currently recruiting and is a global phase 3 randomized controlled trial in patients with germline BRCA1/2 mutations and high-risk, HER2-negative operable breast cancer who have completed definitive local therapy and neoadjuvant or adjuvant chemotherapy. Patients with high-risk disease (eg, residual disease) are randomized to olaparib 300 mg twice daily or placebo for 1 year. The primary endpoint is invasive disease-free survival. Another PARP inhibitor, rucaparib is currently being tested in a phase 1 trial (ClinicalTrials.gov Identifier: NCT03542175) in combination with postoperative radiation therapy in patients with triple-negative breast cancer and residual disease after neoadjuvant chemotherapy. While we eagerly await results of these studies, it is important to keep in mind that the use of PARP inhibition in advanced ovarian and breast cancers has taught us that most tumors ultimately develop resistance. Long-term follow-up of these early-stage trials will be needed to fully assess the utility of PARP inhibition in primary breast cancer.

Question

How do you think germline mutations in the homologous recombination pathway genes could contribute to PARP inhibitor sensitivity, if at all?

Answer

Homologous recombination repair deficiency (HRD) attributable to germline BRCA1/2 mutations is present in approximately 15% of triple-negative breast cancers. In the absence of germline BRCA1/2 mutations, HRD is present in up to 40% of triple-negative breast cancers. The data supporting HRD status as a predictor of clinical response are mixed. Post-hoc observations have suggested that HRD-high tumors may be more sensitive to platinum chemotherapy, however, definitively powered trials are needed.

The GeparOLA study (ClinicalTrials.gov Identifier: NCT02789332) was a phase 2 trial in patients with HRD-high tumors or somatic or germline BRCA1/2 mutations. Patients were randomized to receive either paclitaxel plus olaparib or paclitaxel plus carboplatin, and all patients subsequently received epirubicin and cyclophosphamide followed by surgery. The primary endpoint was pathological complete response (pCR) rate. While the pCR rate was numerically better in the olaparib arm [than] in the paclitaxel/carboplatin arm (55.1%; 90% CI, 44.5%-65.3% vs 48.6%; 90% CI, 34.4%-63.2%), the primary endpoint was not met. Interestingly, the benefit of olaparib appeared to be stronger in patients with HRD-high tumors and no BRCA mutations compared with those with BRCA mutations.

More data are needed to assess the predictive value of HRD status for response to PARP inhibition. Early data particularly support further studies of HRD status in predicting response to PARP inhibition for patients without germline BRCA1/2 mutations.

Question

The addition of veliparib to carboplatin/paclitaxel in BROCADE3 (ClinicalTrials.gov Identifier: NCT02163694) significantly improved progression-free survival (PFS), but not overall survival (OS). What do you make of these seemingly discordant survival findings?

Answer

In BROCADE3, patients were randomized to veliparib plus chemotherapy vs placebo plus chemotherapy. After chemotherapy was stopped, veliparib or placebo were continued in each respective arm. While the median PFS benefit in the veliparib arm was significantly improved compared with the placebo arm, the magnitude of benefit was small — only about 2 months in the investigator-assessed analyses. Importantly, the response rates between the 2 arms were similar, whereas the durability of response was longer in the veliparib arm. This suggests that veliparib may have greater utility as a monotherapy sequenced after chemotherapy, rather than in combination with chemotherapy. Longer-term follow-up is needed to assess overall survival.

Question

Extended follow-up for OlympiAD showed that OS did not differ significantly between the treatment arms studied, but that there was an OS benefit that was “suggested” by the data. What does this really mean for patients?

Answer

Firstly, it is important to note that OS was not the primary endpoint of the OlympiAD study (ClinicalTrials.gov Identifier: NCT02000622) and, therefore, the study was not powered to assess OS. Nonetheless, no significant difference in OS was observed between treatment arms. In preplanned subset analyses, median OS was 7.9 months longer in the olaparib arm for patients who had not received prior chemotherapy for metastatic breast cancer. This observation is consistent with earlier studies in which olaparib was more effective in earlier lines of treatment. Future studies that test olaparib in the first-line setting are needed to confirm these observations. Ultimately, the data thus far suggest that if olaparib is used, it should be administered earlier in the treatment course rather than later.

Question

There was a recent warning from the US Food and Drug Administration that cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors could cause interstitial lung disease (ILD) and pneumonitis in select breast cancer patient groups. Would this warning influence your prescribing practices?

Answer

Postmarket analyses revealed that approximately 1% to 3% of patients treated with CDK 4/6 inhibitors developed ILD or pneumonitis ranging from mild to fatal (in <1% of patients). Alarmingly, some patients had no risk factors for lung disease. However, it is important to remember the significant benefit of CDK 4/6 inhibitors, including an approximate 2-fold increase in median PFS compared with endocrine therapy alone and overall survival benefit in some settings.

As such, the identification of this rare adverse effect has not influenced my use of CDK 4/6 inhibitors. Nonetheless, I now discuss this rare side effect with patients and may order pulmonary function testing and consultation with a pulmonologist for patients who develop respiratory symptoms while on CDK 4/6 inhibition therapy or prior to initiation of CDK 4/6 inhibitors in patients with a history of lung disease.

Question

A recent study presentation² found that the use of breast radiotherapy (as therapy and prevention) should be considered safe in the gBRCA population as it relates to secondary malignancies. What factors would likely influence the decision to administer radiotherapy?

Answer

A rare adverse effect of breast radiation is secondary malignancies, primarily sarcomas or thyroid cancer. It has been hypothesized that germline BRCA1/2 mutations may increase this risk. In this retrospective study, over 200 patients with germline BRCA1/2 mutations who received breast irradiation for breast cancer treatment were included. Only 1 patient developed a malignancy within the radiation field (papillary thyroid carcinoma). Therefore, the authors concluded that breast irradiation did not increase risk of secondary primary malignancies in germline BRCA1/2 mutation carriers. Notably, another study demonstrated that addition of prophylactic irradiation of the contralateral breast in germline BRCA1/2 mutation carriers receiving radiation for breast cancer significantly reduced the risk or delayed onset of contralateral breast cancers (PMID: 30475942). Longer-term follow-up is needed to assess risk of second primary malignancies in this study. Current data do not support withholding radiotherapy for patients with germline BRCA1/2 mutations.