Encouraging outcomes were achieved in patients with BRCA-mutated ovarian cancer who received neoadjuvant treatment with olaparib in a feasibility study led by Shannon N. Westin, MD, MPH, Professor in the Department of Gynecologic Oncology and Reproductive Medicine at The University of Texas MD Anderson Cancer Center, Houston. Dr. Westin reported the findings of the Neoadjuvant Olaparib Window (NOW) trial at the Society of Gynecologic Oncology (SGO) 2023 Annual Meeting on Women’s Cancer.¹ This novel approach included two cycles of the PARP inhibitor olaparib, followed by surgery and, for most patients, chemotherapy in a population of patients with ovarian cancer and a germline mutation in BRCA1, BRCA2, RAD51C, or PALB2.

“The NOW trial demonstrated that neoadjuvant treatment with olaparib is feasible in germline-mutant ovarian cancer, with very intriguing surgical outcomes after only two cycles of therapy.”

— Shannon N. Westin, MD, MPH

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“The NOW trial demonstrated that neoadjuvant treatment with olaparib is feasible in germline-mutant ovarian cancer, with very intriguing surgical outcomes after only two cycles of therapy,” Dr. Westin said. “Of note, patients were excited about the opportunity to avoid chemotherapy if safe and effective.”

Describing the rationale for NOW, Dr. Westin said: “We know the use of PARP inhibitors as maintenance in the front-line treatment of ovarian cancer is absolutely the standard of care, with the greatest clinical impact noted in patients with the presence of a biomarker. As with any success in drug development, we wondered if there was an opportunity to move these agents earlier in the treatment continuum.”

Feasibility was demonstrated in the study of 15 patients, as 100% were able to receive the planned two cycles. Of the 93% of participants able to undergo subsequent surgery, all achieved optimal tumor reduction. Among patients who received the two olaparib cycles followed by surgery and adjuvant chemotherapy, 85% had no evidence of gross disease at the completion of all treatment, Dr. Westin reported.

About NOW

The benefit of olaparib in the neoadjuvant setting was evaluated in the single-arm, open-label pilot NOW study of patients with advanced-stage, high-grade epithelial ovarian, peritoneal, or fallopian tube carcinoma not eligible for primary tumor–reductive surgery. All patients had a germline mutation in BRCA1 or BRCA2, RAD51C or RAD51D, or PALB2.

The primary objective was the feasibility of olaparib in the neoadjuvant setting, defined by unacceptable toxicity (dose interruption > 2 weeks or two dose reductions) or disease progression. The intervention would be deemed feasible if 10 patients could proceed immediately to tumor-reductive surgery.

The study included 51 patients who underwent genetic testing, of whom 20 were found to have a relevant mutation and 15 ultimately were treated with olaparib. The study’s proportion of underrepresented minorities was 27%; 40% had stage IV disease, and 73% had a BRCA1 mutation (other mutations were present but less frequent).

Prior to treatment, patients had tissue collected and underwent germline testing. If found to be eligible, patients received two 28-day cycles of olaparib followed by response assessment with imaging and CA-125 measurement. If deemed amenable to surgery, patients proceeded immediately to surgery; if they responded but were not amenable to surgery or if they had progressive disease, patients started chemotherapy with paclitaxel and carboplatin and then underwent surgery if possible. Following surgery, patients received adjuvant paclitaxel/carboplatin followed by olaparib maintenance per patient and provider discretion.

Dr. Westin indicated that germline testing was expedited in this study, with STAT panel testing provided through Invitae. Ideally, any patient with suspected ovarian, peritoneal, or fallopian tube cancer had blood sent for testing after the first clinic visit and was seen by a genetic counselor. The company provided close tracking for study patients, with a median turnaround of 10 days. Patients who tested negative for BRCA1/2 had reflex testing for the full genetic panel.

Surgery Feasible in 87%

Surgery after olaparib was possible for 13 patients (86.6%); 1 patient underwent surgery after receiving chemotherapy, and 1 patient was unable to have surgery because of worsening performance status. No gross residual disease after surgery was reported in 85% of the patients who had two cycles of olaparib plus surgery. All patients had optimal tumor-reductive surgery, and one patient achieved a pathologic complete response, Dr. Westin reported.

The median number of chemotherapy cycles was six. “However, as the study progressed, we saw a reduction in the number of cycles, including for three patients who went immediately back to olaparib therapy after surgery with no intervening chemotherapy,” she said.

Among 13 patients with measurable disease, the partial response rate was 53.8%, and none of these patients had progressive disease. Of note, after two cycles of olaparib, 93% of patients had a reduction in CA-125 levels, and for 75% of patients, this reduction was 75%. The median best percent change in CA-125 was 81%, she reported. At a median follow-up of 11.7 months, median progression-free survival was not reached, and the 12-month progression-free survival probability was 81%.

Adverse events were as expected for PARP inhibitor therapy, with the most common toxicities being abdominal pain, constipation, and anemia, but only anemia was a grade 3 event (20%). One patient needed a dose reduction and one, a dose interruption.

Further Discussion

A listener at the session applauded the investigators for their “brave” and “out-of-the-box” approach. Another listener wondered if the study challenged the concept of “equipoise” in testing new approaches—ie, that there is uncertainty about whether the experimental treatment or the standard of care will be more beneficial.

Dr. Westin responded that NOW was designed as a feasibility study in a small cohort of patients “for that very reason. Safety was the utmost priority. We had a lot of discussions back and forth with our [institutional review board] around what success looks like, how closely we should monitor these patients, and how quickly we should make the transition to chemotherapy.”

She said the investigators made sure patients understood that chemotherapy was “absolutely the standard of care,” but there was solid evidence that PARP inhibitors reduce tumors, an observation that would only be stronger in untreated patients with platinum-sensitive disease that has not developed resistance. She said patients appreciated the reassurance that they would receive chemotherapy right away should their response to olaparib be suboptimal.

“I’m obviously very hopeful that these patients are cured, based on the high proportion who were able to get a resection with no residual disease,” Dr. Westin commented, but she shared this comment during questioning: “The idea of initial cytoreduction [with chemotherapy] and then transitioning to olaparib as adjuvant therapy may still be a more ideal choice…. We need to look at a larger patient population to assess that.” 

DISCLOSURE: Dr. Westin has served as a consultant to AstraZeneca, Bayer, Caris, Clovis Oncology, Eisai, EQRX, GSK, ImmunoGen, Eli Lilly, Merck, Mersana, NGM Bio, Nuvectis, Roche/Genentech, Seagen, Vincerx, Zentalis, and ZielBio.

REFERENCE

1. Westin SN, Michael V, Fellman BM, et al: Neoadjuvant window trial in newly diagnosed BRCA mutant ovarian cancer. Society of Gynecologic Oncology 2023 Annual Meeting on Women’s Cancer. Presented March 26, 2023.