Neoadjuvant Olaparib Combo Safe in Breast Cancer

In Clinical Studies News by Barbara Jacoby

By: Jason M. Broderick


Adding the PARP inhibitor olaparib (Lynparza) to neoadjuvant platinum based-chemotherapy was determined to be a safe treatment for patients with triple-negative breast cancer (TNBC), as well as for patients with breast cancer whose tumors harbor germline BRCA mutations, according to preliminary safety data from the phase II/III PARTNER trial.

“The majority of adverse events (AEs) were grade 1/2, only 5% of the AEs were grade 3 or greater. This is a tolerable regimen, it’s manageable—toxicity is not massively increased by the addition of olaparib to the chemotherapy regimen,” lead study author Karen Pinilla Alba, MD, a medical oncologist and clinical research fellow at the University of Cambridge, said in an interview with OncLive® at the 2019 San Antonio Breast Cancer Symposium (SABCS).

PARTNER is a randomized international 3-stage trial—stages 1 and 2 evaluated the safety of the olaparib regimen and determined the optimal treatment schedule, and stage 3 will evaluate the efficacy of the regimen with a primary endpoint of pathologic complete response (pCR).

To enroll on the study, patients must be aged 16 to 70; have an ECOG performance status of 0 or 1; have histologically confirmed invasive breast cancer; have confirmed ER-negative and HER2-negative disease with a TNBC basal phenotype or have germline BRCA-positive breast cancer, regardless of hormone status; and have clinical stage T1-4 N0-2 disease (tumor or node diameter >10 mm).

The recruitment goal for the trial is 750 patients, including at least 180 patients with BRCA-positive tumors. Stages 1 and 2 are complete, while recruitment is ongoing for stage 3.

Stages 1 and 2 involved a 1:1:1 randomization of patients to a control arm of 4 cycles of neoadjuvant paclitaxel plus carboplatin or the same chemotherapy regimen plus olaparib at 150-mg orally twice daily on days 2 to 10 every 3 weeks (research arm 1), or olaparib at 150-mg orally twice daily on days 3 to 14 every 3 weeks (research arm 2). In the study design, after completing their initial regimen, all patients receive anthracycline-based chemotherapy followed by surgery.

Between June 2016 and April 2018, the study accrued 159 patients across the 3 arms of stage 1 and 2, with 53 patients randomized to each arm. In research arm 1, 7 patients were aged <40 years and 15 patients were aged 60 to 70 years. The ECOG performance score was 0 for 48 patients and 1 for 5 patients. Eleven patients were BRCA-positive, 88.7% had a tumor size ≤ 50 mm, 32.1% had axillary node involvement, and 68% had a TILs rate <60%.

In research arm 2, 13 patients were aged <40 years and 14 patients were aged 60 to 70 years. The ECOG performance score was 0 for 45 patients and 1 for 8 patients. Seven patients were BRCA-positive, 92.5% had a tumor size ≤50 mm, 34% had axillary node involvement, and 68% had a TILs rate <60%.

In the control arm, 13 patients were aged <40 years and 7 patients were aged 60 to 70 years. The ECOG performance score was 0 for 51 patients and 1 for 2 patients. Seven patients were BRCA-positive, 90.6% had a tumor size ≤50 mm, 30.2% had axillary node involvement, and 68% had a TILs rate <60%.

In a poster presented at SABCS, Pinilla Alba and coinvestigators shared pooled safety data for the 106 patients from stages 1 and 2 of the trial who were assigned to either research arm 1 or 2. Data were not included for the 53 patients in the control arm.

In the research arms, 94% of arm 1 and 96% of arm 2 received 4 cycles of olaparib. Across all patients in the pooled analysis, 95.6% of AEs were grade 1/2 and 4.5% were grade 3/4. Over half (54%) of patients had at least 1 grade ≥3 AE during treatment in the research arms.

There was no significant difference between the research arms in terms of safety (P = .846). Hematologic grade ≥3 AEs occurred in 33% of the research arms and 36% of patients in the research arms experienced nonhematologic grade ≥3 AEs. Among patients treated in the research arms, 10% (n = 11) had grade 3/4 toxicities that appeared to be associated with olaparib treatment. Olaparib had to be discontinued in 2 patients due to AEs.

The most common grade ≥3 AEs in the research arms for cycles 1 to 4 included decreased neutrophil count (17% in research arm 2 vs 26% in research arm 1), anemia (19% vs 21%, respectively), fatigue (8% vs 11%), infection (9% vs 8%), decreased platelet count (9% vs 4%), hypertension (6% each), diarrhea (8% vs 2%), dyspnea (6% vs 0%), sensory neuropathy (4% vs 2%), febrile neutropenia (2% vs 4%), and ALT increase (0% vs 6%).Serious AEs across all grades occurred in 30.2% of both research arm 1 and research arm 2. Grade 3 or 4 serious adverse reactions occurred in 7.5% (n = 4) of research arm 1 and 9.4% (n = 5) of research arm 2. Grade 3 sensory neuropathy was reported in 5 patients. There was 1 case of grade 4 motor neuropathy. There were no AE-related deaths.

Although the researchers did not provide the safety data from the control arm Pinilla Alba said, “I think it’s fair to say that the proportion of grade 3 AEs that were reported did not exceed what is already known in terms of side effects from previous clinical trials that assessed platinum-based chemotherapy in the neoadjuvant setting.”

With no significant differences between the safety profiles for the 2 arms, the researchers decided to drop the research arm 1 schedule from the trial and just proceed with the schedule from research arm 2.

Regarding initial efficacy data, Pinilla Alba said the trial should be fully enrolled by the end of 2020, with data likely to be reported about 6 months after that.

Olaparib is currently approved by the FDA for the treatment of patients with germline BRCA-positive, HER2-negative metastatic breast cancer who have previously received chemotherapy. Additionally, HR-positive patients should have prior endocrine therapy or not be considered appropriate for such treatment. Updated data from the pivotal phase III OlympiAD trial on which the approval was based were also reported this year at SABCS.

Pinilla Alba K, McMurtry E, Vallier A-L, et al. Preliminary safety data from stage 1 and 2 of the phase II/III PARTNER trial: Addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients. Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14; San Antonio, TX. Abstract P3-10-05.