Neoadjuvant olaparib feasible in BRCA-mutated ovarian cancer

Neoadjuvant treatment with the PARP* inhibitor olaparib yielded encouraging outcomes in patients with BRCA-mutated ovarian cancer, with all participants completing two cycles of therapy followed by surgery in the NOW trial presented at SGO 2023.

Of the 93 percent of women who underwent subsequent surgery, all achieved optimal tumour reduction.

“Neoadjuvant treatment with olaparib was feasible in germline mutant ovarian cancer with very intriguing surgical outcomes after only two cycles of therapy,” said lead study author Dr Shannon Westin from the Department of Gynecologic Oncology and Reproductive Medicine at The University of Texas MD Anderson Cancer Center in Houston, Texas, US. “Importantly, patients were very excited about the potential to avoid chemotherapy, if safe and effective.”

“This study provides a potential template for how we might vet targeted therapies earlier in the treatment continuum,” she added.

The use of PARP inhibitors as maintenance in the frontline treatment of ovarian cancer is the standard of care, with the greatest impact in patients with the presence of a biomarker, said Westin. “But then we wondered if there was an opportunity to move these agents earlier in the treatment continuum.”

Olaparib in the neoadjuvant setting

The NOW study sought to evaluate the benefit of neoadjuvant olaparib in patients with advanced-stage, high-grade epithelial ovarian, peritoneal, or fallopian tube carcinoma who were ineligible for primary tumour-reductive surgery (TRS).

All patients had a germline mutation in BRCA1 or BRCA2, RAD51C or RAD51D, or PALB2. Median age was 56 years and 40 percent had stage IV disease. Fifteen with BRCA-mutated ovarian cancer were ultimately treated with olaparib 300 mg twice daily for two 28-day cycles and monitored for toxicity.

The primary endpoint was feasibility of neoadjuvant olaparib, defined by unacceptable toxicity (dose interruption for >2 weeks or two dose reductions) or disease progression. Intervention would be deemed feasible if 10 patients could proceed to TRS immediately.

Following germline testing, eligible patients received olaparib and were assessed for responses through imaging and CA-125 measurement. Those without disease progression after olaparib treatment were considered for TRS. Responders not amenable to TRS or had progressive disease received chemotherapy with paclitaxel and carboplatin first, and then surgery if feasible. 

After surgery, patients received adjuvant paclitaxel/carboplatin, followed by olaparib maintenance.

Those who underwent immediate TRS received postoperative adjuvant therapy at the clinician/patient discretion.

No residual disease in majority of patients

“Surgery after olaparib was feasible for 87 percent of patients,” reported Westin. One patient underwent surgery following chemotherapy. “Importantly, 85 percent of patients had no gross residual disease.”

“I am hopeful these patients are cured based on the high proportion who were able to get a no-residual-disease resection,” she added.

Looking at responses, eight percent had a pathologic complete response, 53.8 percent had a partial response, 46.2 percent had stable disease. Not one experienced disease progression.

After two cycles of olaparib, 93 percent of patients had a reduction in CA-125 levels. For 75 percent of patients, the reduction was at 73 percent.

At a median follow up of 11.7 months, median progression-free survival was not reached. So far, only two patients experienced disease progression following adjuvant therapy.

“The decision to undergo adjuvant therapy lies with the physician and the patient, but as the study progressed, we did see a reduction in chemotherapy cycles,” said Westin. “Three patients actually went back to olaparib immediately after surgery, with no intervening chemotherapy.”

Adverse events were as expected for a PARP inhibitor therapy, with the most common being abdominal pain (47 percent), constipation (27 percent), anaemia (20 percent), nausea (13 percent), and pain (13 percent). Three patients experienced grade 3 anaemia.

Potential new role for olaparib

The study challenges the concept of clinical equipoise in testing new strategies for BRCA-mutated ovarian cancer.

“There could be a new role for neoadjuvant PARP inhibitor therapy in place of chemotherapy in these patients,” commented Dr Gina Mantia-Smaldone from the Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, US.

“Chemotherapy was absolutely the standard of care,” Westin said. “But there was evidence that PARP inhibitors reduce tumours. In our study, patients received chemotherapy if response to olaparib was suboptimal.”

Still in certain patients, surgery with chemotherapy, and then transitioning to adjuvant olaparib may still be a more ideal choice, she pointed out. “We need a larger population to assess that.”

Olaparib is approved as maintenance for BRCA-mutated ovarian cancer in the recurrent and front-line setting and for the treatment of BRCA-mutated ovarian cancer in patients who have received multiple prior lines of chemotherapy.