Neoadjuvant Olaparib Proves Feasible, Aids Optimal Resection in BRCA-Mutant Ovarian Cancer

Neoadjuvant treatment with olaparib (Lynparza) prior to surgical resection and adjuvant chemotherapy was well tolerated and led to a 100% optimal resection rate in patients with newly diagnosed, BRCA-mutant ovarian, primary peritoneal, or fallopian tube cancer, according to findings from the phase 1 NOW trial (NCT03943173) presented at the 2023 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer.^1,2

With a follow-up of 11.7 months (range, 2.0-32.2), the estimated 12-month progression-free survival rate was 81% (42%-95%).

“Surgical outcomes [were] outstanding with only 2 cycles, even in stage IV disease. [Additionally, we saw an] expected safety profile during olaparib window treatment,” presenting study author Shannon N. Westin, MD, MPH, professor in the Department of Reproductive Medicine at The University of Texas MD Anderson Cancer Center in Houston, said in a presentation.

“This study provides a potential template for how we might vet targeted therapies earlier in the treatment continuum. As drug options increase, it is encouraging to see opportunities for patients to get testing at diagnosis and receive targeted therapy in lieu of or in addition to chemotherapy,” Westin added in a press release.2

NOW is a single-arm, open-label pilot study.2 The primary objective was to determine the feasibility of administering olaparib in the neoadjuvant setting for patients with advanced, high-grade, BRCA-mutant ovarian cancer.1 Secondary objectives included efficacy and the proportion of patients able to undergo interval tumor reductive surgery; complete pathologic response; and toxicity. 

To be eligible for enrollment, patients had to have a germline BRCA1/2, RAD51C/D, or PALB2 mutation; high-grade serous histology; disposition to neoadjuvant chemotherapy with planned interval tumor reductive surgery; measurable or evaluable disease; and no prior treatment. Additional criteria included an ECOG performance status from 0 to 2; adequate normal organ and marrow function; Hg at or above 9; absolute neutrophil count above 1.5; platelet count above 100; bilirubin at or below 1.5; aspartate/alanine aminotransferase at or below 2.5 of the upper limit of normal; and creatinine clearance at or above 40 ml/min.

A total of 61 patients underwent screening and 51 underwent genetic testing. Of these patients, 20 had a mutation and 15 received olaparib.

Testing was provided to any patient with suspected ovarian, peritoneal, or fallopian tube cancer through Invitae’s STAT BRCA1/BRCA2 panel. All patients were seen by a genetic counselor, and company-provided tracking was provided for patients. The median turnaround time for results was 10 days (range, 5-15).

Per the study protocol, patients received olaparib in the neoadjuvant setting. Patients who experienced disease progression or response that was not amenable to surgery proceeded to chemotherapy with paclitaxel and carboplatin followed by surgery, additional chemotherapy, and PARP inhibitor maintenance. Patients who derived response from neoadjuvant olaparib underwent surgery, which was followed with chemotherapy and PARP inhibitor maintenance at the investigator’s discretion. 

The median patient age was 56 years (range, 44-88) and most patients were White (73.3%) and non-Hispanic/Latina (80%). Most patients had stage IIIC disease (60%), followed by IVA (20%) and IVB (20%). BRCA1 was the most common mutation (73.3%), followed by BRCA2 (13.3%), RAD51C (6.7%), and PALB2(6.7%). 

The median number of olaparib cycles was 2 (range, 2-2), and the median number of chemotherapy cycles was 6 (range, 0-6). Among 13 evaluable patients, the partial response rate was 53.8% and 46.2% of patients experienced stable disease. Most patients proceeded to surgery immediately after olaparib (86.6%), whereas 6.7% did not undergo surgery at all and 6.7% underwent interval surgery after chemotherapy.

Among the patients who underwent surgical debulking (n = 14), most achieved optimal results with no gross residual disease (85.7%). The remaining patients achieved optimal resection with less than 1 cm of residual disease.

Regarding adjuvant therapy, patients received paclitaxel/carboplatin for 6 cycles of (n = 7), 4 cycles (n = 1), or 3 cycles (n = 3). One patient’s cycle number was pending at the time of analysis, and 3 patients did not receive chemotherapy and instead switched to a PARP inhibitor.

Notably, one patient each received adjuvant chemotherapy, progressed on chemotherapy, and experienced a decline in performance status on chemotherapy.

Additionally, 93% of patients had a 25% reduction in CA125 levels; 87% had a 50% decrease and 73% had a 75% decrease. The median best percentage change was 81% (range, -98.1%–35%).

Regarding safety, common adverse effects included abdominal distention (all grade, 6.7%; n = 1), abdominal pain (all grade, 33.3%; n = 5), anemia (all grade, 20%; n = 3; grade 3/4, n = 3), anorexia (all grade, 6.7%), back pain (all grade, 6.7%), constipation (all grade, 26.7%; n = 4), dyspnea (all grade, 6.7%), fatigue (all grade, 6.7%), nausea (all grade, 13.3%; n = 2), and pain (all grade, 13.3%).

Dose interruption occurred in 1 patient and treatment was held for 7 days. The same patient received dose reduced olaparib because of grade 3 anemia.

“Molecular assessment of pre- and post-treatment changes in circulating tumor DNA and tissue biomarkers [is ongoing],” Westin concluded.

Disclosures: Dr Westin reports research support from AstraZeneca, AvengeBio, Bayer, Clovis Oncology, GSK, Mereo, Novartis, Roche/Genentech, and Zentalis; and serving as consultant for AstraZeneca, Bayer, Caris, Clovis Oncology, Eisai, EQRX, GSK, ImmunoGen, Lilly, Merck, Mersana, NGM Bio, Nuvectis, Roche/Genentech, Seagen, Vincerx, and Zentalis.

References

1. Westin S. NOW: neoadjuvant olaparib window trial in newly diagnosed BRCA mutant ovarian cancer. Presented at: 2023 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer; March 25-28; Tampa, Florida. Abstract 138.
2. Study finds intriguing outcomes in ovarian cancer patients treated with PARP inhibitors before surgical intervention and subsequent chemotherapy. News release. FirstWord Pharma. March 26, 2023. Accessed March 28, 2023. https://firstwordpharma.com/story/5720394