New Role for Olaparib in BRCA Ovarian Cancer in Neoadjuvant Setting 

Roxanne Nelson, RN, BSN

March 30, 2023

Olaparib (Lynparza) is a PARP inhibitor that is already approved for use as a first-line maintenance therapy for ovarian cancer, in particular in patients with BRCA mutations, but a new study suggests there could be another extension to the indication: neoadjuvant use prior to surgery.

New results show that giving olaparib in the neoadjuvant setting is feasible, with all participants completing the planned two cycles. In addition, of the 93% of women who underwent subsequent surgery, all achieved optimal tumor reduction.

"There were very intriguing outcomes after only two cycles," said lead author Shannon N. Westin, MD, MPH, professor, Department of Gynecologic Oncology and Reproductive Medicine at the University of Texas MD. Anderson Cancer Center, Houston. "This study provides a potential template for how we might vet targeted therapies earlier in the treatment continuum."

Westin presented the findings at the Society of Gynecologic Oncology (SGO) 2023 Annual Meeting on Women's Cancer.

"The use of PARP inhibitors as frontline maintenance in ovarian cancer is the absolute standard of care," explained Westin, "With the greatest impact noted in patients with the presence of a biomarker."

"But as with any success in drug development, we  wondered if there was an opportunity to move these agents earlier in the treatment continuum," she added.

Favorable Outcomes

Westin and colleagues conducted a single-arm, open-label pilot study of olaparib monotherapy for patients with advanced-stage, high-grade epithelial ovarian, peritoneal, or fallopian tube carcinoma.

All patients had germline mutation in BRCA1 and BRCA2 and the study also included those with RAD51C or PALB2 mutations. The median age of the cohort was 56 years and 40% had stage IV disease.

The design of the trial was a little complicated, Westin noted. All participants received two cycles of olaparib at 300 mg orally twice daily, and then were assessed with imaging. Patients without disease progression were considered for tumor reductive surgery (TRS), while those deemed not amenable to surgery or with progressive disease received chemotherapy. Patients who underwent immediate TRS received postoperative adjuvant therapy at the clinician/patient discretion.

The primary objective of the trial was to determine feasibility of olaparib in the neoadjuvant setting, with feasibility defined as the ability to receive two cycles of olaparib without unacceptable toxicity or disease progression.

A total of 15 patients were treated with olaparib, and all were evaluable for toxicity, but only 13 were evaluable for response. Of the evaluable group, 83% had surgery immediately afterwards, Westin explained.

When looking at outcomes, 1 patient (8%) had a pathologic complete response, 7 patients (53.8%) had a partial response, 6 (46.2%) had stable disease, and no patients  experienced disease progression after treatment with olaparib. After the completion of all therapies, 85% had no evidence of disease.

After surgical debulking (n = 14), 12 patients (85.7%) had an optimal outcome (no gross residual), 2 patients (14.3%) had a optimal outcome with <1 cm residual, and no outcomes were suboptimal.

Westin also pointed out that 93% of patients experienced a CA-125 reduction, with 73% of patients achieving a 75% decrease in levels of this biomarker.

At a median follow up of 11.7 months, median progression-free survival has not yet been reached.

To date, only two patients have experienced disease progression following adjuvant therapy (one immediately at completion of adjuvant therapy and one at 3 months after therapy).

"Adjuvant therapy was up to the treating physician and patient, but we did see a trend as the study progressed in a reduction in chemotherapy cycles," said Westin. "Three patients went immediately back to olaparib with no chemotherapy."

Adverse events during olaparib were as expected, with abdominal pain (47%), constipation (27%), anemia (20%), nausea (13%), and pain (13%) observed most commonly. The only grade 3/4 events reported were in three patients (20%) who experienced grade 3 anemia.

Westin added that patients are interested in PARP inhibitor monotherapy, and that there is ongoing molecular assessment of pre- and post-treatment changes in ctDNA and tissue biomarkers.

Possible Role as Neoadjuvant Therapy

Approached by Medscape Medical News for an independent comment, Gina Mantia-Smaldone, MD, associate professor, Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, noted that there was a great deal of excitement generated over the results of this study.

"Of the 14 patients who went to surgery, 86% of patients had a complete cytoreduction with 1 patient who had a pathologic complete response," she said. "This study suggests a role of neoadjuvant PARP inhibitor therapy in place of chemotherapy for patients with newly diagnosed ovarian cancer and germline mutations in BRCA1, BRCA2, RAD51C, RAD51D, or PALB2 genes."

The study was supported by AstraZeneca, manufacturer of olaparib. Westin reported relationships with AstraZeneca, AvengeBio, Bayer, Caris, Clovis Oncology, Eisai, EQRX, GSK, ImmunoGen, Lilly, Merck, Mereo, Mersana, NGM Bio, Novartis, Nuvectis, Roche/Genentech, Seagen, Vincerx, and Zentalis. Mantia-Smaldone reports no relevant financial relationships.

Society of Gynecologic Oncology (SGO) 2023 Annual Meeting on Women's Cancer. Presented March 26, 2023.

Roxanne Nelson is a registered nurse and an award-winning medical writer who has written for many major news outlets and is a regular contributor to Medscape.

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