Olaparib Delivers PFS Benefit to Patients with gBRCA+, HER2– Metastatic Breast Cancer, Independent of ER Status

Karen A. Gelmon, MD

Olaparib (Lynparza) was associated with consistent clinical benefit in patients with germline BRCA-mutated, HER2-negative metastatic breast cancer, regardless of their estrogen receptor (ER) expression level, according to data from a post-hoc analysis of the phase 3b LUCY trial (NCT03286842) presented at the 2023 ESMO Breast Cancer Annual Congress.¹

Findings showed that patients with an ER expression of less than 1% (n = 117) achieved a median progression-free survival (PFS) of 6.8 months (95% CI, 5.5-9.0). Those with an ER expression between 1% and 10% (n = 29) had a median PFS of 8.3 months (95% CI, 4.5-12.6), and patients with an ER expression of more than 10% (n = 105) experienced a median PFS of 8.4 months (95% CI, 7.6-11.0).

The median overall survival (OS) was 20.1 months (95% CI, 16.5-26.9), 22.9 months (95% CI, 13.0-35.1), and 27.4 months (95% CI, 23.0–not reached) in patients with an ER expression of less than 1%, an ER between 1% and 10%, and an ER of more than 10%, respectively. Study authors noted that the improved OS for patients with hormone receptor–positive breast cancer relative to those with triple-negative breast cancer was consistent with findings for patients given standard chemotherapy alone in the phase 3 OlympiAD trial (NCT02000622).

“Real-world results of the phase 3b LUCY trial indicate that olaparib’s clinical effectiveness in patients with germline BRCA-mutated, HER2-negative metastatic breast cancer is independent of ER expression status,” lead study author Karen A. Gelmon, MD, a medical oncologist at the University of British Columbia, in Vancouver, British Columbia, Canada, and colleagues, wrote in a poster presentation of the data.

In January 2018, the FDA approved olaparib for the treatment of patients with germline BRCA-positive, HER2-negative metastatic breast cancer have previously received chemotherapy, based on data from OlympiAD.² The LUCY trial evaluated the real-world efficacy and safety of the PARP inhibitor in patients with germline or somatic BRCA-mutated, HER2-negative metastatic breast cancer, and the final analysis of the study showed that the median PFS of 8.2 months for the overall population was consistent with median PFS of 7.0 months reported from the olaparib arm of OlympiAD.^3,4

The post-hoc analysis further examined the efficacy of olaparib in patients with germline BRCA-mutated, HER2-negative metastatic breast cancer by ER expression status.

LUCY enrolled patients at least 18 years of age or older with germline or somatic BRCA-mutated, HER2-negative metastatic stage IV breast cancer who were fit to receive single-agent chemotherapy and were administered no more than 2 prior cycles of chemotherapy. Previous treatment with taxane- and/or anthracycline-based chemotherapy in the adjuvant or metastatic setting was required. At least 1 prior line of endocrine therapy in the adjuvant or metastatic setting was required unless patients were not suitable for endocrine therapy.

All patients in the single-arm, open-label trial were treated with 300 mg of olaparib twice daily until disease progression, unacceptable toxicity, or other protocol-specified discontinuation criteria were met.

In the post-hoc subgroup analysis, ER expression was determined by immunohistochemistry. The analysis examined investigator-assessed PFS, OS, clinical response rate (CRR), duration of clinical response (DOCR), time to first subsequent treatment or death (TFST), and time to second subsequent treatment or death (TSST).

Study authors noted that baseline characteristics were generally similar across the 3 ER expression subgroups. The median age was 44.0 years (range, 22-69), 45.0 years (range, 28-68), and 47.0 years (range, 25-75) in the ER expression of less than 1%, ER expression between 1% and 10%, and ER expression of more than 10% groups, respectively. Notably, 4 men were included in the ER expression more than 10% subgroup, and all patients in the other 2 groups were female.

The majority of patients had an ECOG performance status of 0 in the ER expression of less than 1% group (70.9%), the ER expression between 1% and 10% group (65.5%), and the ER expression of more than 10% group (76.2%).

The median time from first diagnosis of breast cancer to study entry was 29.7 months (range, 4-333), 52 months (range, 5-257), and 58.6 months (range, 11-500) in the ER expression of less than 1%, ER expression between 1% and 10%, and ER expression of more than 10% groups, respectively. The median time from first diagnosis of metastatic breast cancer to study entry for these groups was 4.8 months (range, 0-279), 11.1 (range, 0-83), and 12.5 (range, 0-138), respectively.

In the ER expression of less than 1% group, 78.6% of patients had a germline BRCA1 mutation, 18.8% had a germline BRCA2 mutation, and 1.7% had both. In the ER expression between 1% and 10% group, 34.5% of patients had a BRCA1 mutation, 58.6% had a BRCA2 mutation, and 6.8% had both. For those with an ER expression of more than 10%, BRCA1 mutations were reported in 31.4% of patients, BRCA2 mutations occurred in 65.7%, and both mutations were seen in 1.0%.

Additional data showed that CRRs and DOCR were consistent across ER expression subgroups. The median CRR was 50.9% (95% CI, 41.4%-60.3%), 42.9% (95% CI, 24.5%-62.8%), and 49.0% (95% CI, 39.1%-59.0%) in patients with an ER expression of less than 1%, an ER expression of 1% to 10%, and an ER expression of more than 10%, respectively. The median DOCR in these 3 subgroups was 8.3 months (interquartile range [IQR], 3.8-26.5), 7.2 months (IQR, 5.3-14.1), and 7.4 months (IQR, 4.3-17.7), respectively.

In the ER expression of less than 1% subgroup, 62.4% of patients received a first subsequent anticancer treatment, and the median TFST was 8.7 months (95% CI, 6.8-10.3). The rates of patients who did not receive a first subsequent treatment at 12, 24, and 30 months were 36.4%, 27.1%, and 21.7%, respectively.

Furthermore, 75.9% of patients in the ER expression between 1% and 10% subgroup received a first subsequent treatment, and the median TFST was 9.3 months (95% CI, 7.1-12.6). Additionally, 35.8%, 16.4%, and 16.4% of patients did not receive a first subsequent treatment at 12, 24, and 30 months, respectively. In the ER expression of more than 10% group, 70.5% received a first subsequent treatment with a median TFST of 9.7 months (95% CI, 8.5-11.7). At 12, 24, and 30 months, 38.8%, 21.5%, and 17.2% of patients, respectively, had not received a first subsequent treatment.

Notably, 9.4%, 10.3%, and 9.5% of patients in the ER expression of less than 1%, ER expression between 1% and 10%, and ER expression of more than 10% groups, respectively, died in the absence of first subsequent treatment.

Additionally, 36.8% of patients in the ER expression of less than 1% subgroup received a second subsequent anticancer treatment, and the median TSST was 14.0 months (95% CI, 11.4-17.5). The rates of patients who did not receive a second subsequent treatment at 12, 24, and 30 months were 55.7%, 33.1%, and 27.8%, respectively.

Moreover, 41.4% of patients in the ER expression between 1% and 10% subgroup received a second subsequent treatment, and the median TSST was 14.7 months (95% CI, 12.1-18.7). Additionally, 71.5%, 22.8%, and 19.0% of patients did not receive a second subsequent treatment at 12, 24, and 30 months, respectively.

In the ER expression of more than 10% group, 48.6% received a second subsequent treatment with a median TSST of 14.7 months (95% CI, 13.5-20.4). At 12, 24, and 30 months, 67.3%, 34.9%, and 25.8% of patients, respectively, had not received a second subsequent treatment.

Across the 3 subgroups, 27.4%, 37.9%, and 20.0% of patients, respectively, died in the absence of second subsequent treatment.

“Overall, these results show that olaparib is equally effective in people with HER2-negative metastatic breast cancer and an inherited BRCA mutation, regardless of how much ER is expressed by their cancer,” Gelmon and colleagues concluded.

References

1. Gelmon K, Fasching PA, Delaloge S, et al. Clinical effectiveness of olaparib in BRCA-mutated, HER2-negative metastatic breast cancer (mBC) by ER expression level: subgroup analysis from phase 3b LUCY trial. Presented at: 2023 ESMO Breast Cancer Annual Congress; May 11-13, 2023; Berlin, Germany. Abstract 203P.
2. FDA approves olaparib for germline BRCA-mutated metastatic breast cancer. News release. FDA. January 12, 2018. Accessed May 11, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-olaparib-germline-brca-mutated-metastatic-breast-cancer
3. Robson M, Im SA, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017;377(6):523-533. doi:10.1056/NEJMoa1706450
4. Balmana J, Fasching PA, Delaloge S, et al. Clinical effectiveness and safety of olaparib in BRCA-mutated, HER2-negative metastatic breast cancer in a real world setting: phase 3b LUCY final analysis. Ann Oncol. 2022;33(suppl 3):S205-S206. doi:10.1016/j.annonc.2022.03.193