Olaparib With/Without Cediranib Does Not Improve OS Vs Chemo in Recurrent Platinum-Sensitive Ovarian Cancer

Joyce F. Liu, MD, MPH

The use of olaparib (Lynparza) as a monotherapy or in combination with cediranib did not provide a statistically significance overall survival (OS) benefit compared with standard-of-care platinum-based chemotherapy in patients with recurrent, platinum-sensitive ovarian cancer, according to the final report of survival outcomes from the randomized phase 3 NRG-GY004 trial (NCT02446600).¹

Findings presented during the 2023 ESMO Congress showed that chemotherapy (n = 187) resulted in a median OS of 32.7 months vs 33.5 months with olaparib plus cediranib (n = 189; HR, 1.12; 95% CI, 0.874-1.43; P = .0378) and 31.0 months with olaparib alone (n = 189; HR, 1.27; 95% CI, 0.990-1.62; P = .060).

Further assessment of OS outcomes according to BRCA mutational status showed that patients with a germline BRCA1/2 mutation experienced a numerically higher median OS across all 3 treatment arms. The median OS was 43.2 months, 44.8 months, and 41.3 months in the chemotherapy (n = 44), olaparib/cediranib (n = 45; HR, 1.26; 95% CI, 0.71-2.21), and olaparib monotherapy (n = 45; HR, 1.39; 95% CI, 0.80-2.42) arms, respectively. Conversely, patients without these mutations experienced a median OS of 30.0 months, 29.6 months, and 24.5 months with the chemotherapy (n = 143), olaparib combination (n = 144; HR, 1.07; 95% CI, 0.82-1.40), and olaparib monotherapy (n = 144; HR, 1.24; 95% CI, 0.94-1.63) regimens, respectively.

“When we look at OS, neither olaparib nor the combination of cediranib and olaparib improved OS compared with chemotherapy regardless of germline BRCA status,” lead study author Joyce F. Liu, MD, MPH, stated in an oral presentation of the data. Liu is an associate chief of the Division of Gynecologic Oncology, director of Clinical Research in the Division of Gynecologic Oncology, associate clinical research officer of the Clinical Research Program, and a physician at Dana-Farber Cancer Institute, in Boston, Massachusetts. She is also an associate professor of medicine at Harvard Medical School.

This randomized, open-label, study enrolled patients with measurable or evaluable platinum-sensitive relapsed high-grade serous or high-grade endometrioid ovarian, primary peritoneal, or fallopian tube cancer. Eligible patients were also required to have been treated with up to 1 prior platinum-based chemotherapy and experienced disease recurrence no less than 6 months after their most recent chemotherapy treatment. Key exclusion criteria included prior treatment with a PARP inhibitor or antiangiogenic therapy in the recurrent setting, with the exception of bevacizumab (Avastin).¹

Patients were stratified by germline BRCA status (mutation vs wild-type), prior platinum-free intervals (PFI; 6 to 12 months vs 12 months or longer), and whether they had received prior antiangiogenic therapy (yes vs no). They were randomly assigned 1:1:1 to receive 300 mg of olaparib twice a day, 200 mg of olaparib twice daily and 30 mg of cediranib once daily, or 1 of 3 platinum-doublet chemotherapy regimens per investigator’s choice. Chemotherapy regimens could include carboplatin plus paclitaxel, carboplatin plus gemcitabine, or carboplatin plus liposomal doxorubicin. The olaparib regimens were continuously dosed.

Patients assigned to the chemotherapy arm could continue treatment for as long as medically appropriate. All patients who completed chemotherapy did not receive further therapy and were followed until disease progression.¹ Patients in the olaparib-containing arms continued treatment until disease progression, intolerable toxicity, or withdrawal. Radiographic tumor assessments were done every 9 weeks for 12 months, followed by every 12 weeks until disease progression.

The study’s primary end point was PFS. Key secondary end points included OS, ORR, and the agent’s clinical activity in biomarker-defined populations.¹

Previously reported data from NRG-GY004 showed that neither cediranib plus olaparib or olaparib alone met the primary end point of improved progression-free survival (PFS) vs platinum-based chemotherapy (HR, 0.86; 95% CI, 0.66-1.10; P = .077). However, the regimens did produce similar antitumor activity. The median PFS in the intention-to-treat population was 10.3 months (95% CI, 8.7-11.2), 10.4 months (95% CI, 8.5-12.5), and 8.2 months (95% CI, 6.6-8.7) with chemotherapy, the olaparib combination, and olaparib monotherapy, respectively. Corresponding overall response rates were 71.3% (95% CI, 63.4%-78.1%), 69.4% (95% CI, 61.8%-76.1%), and 52.4% (95% CI, 44.8%-60.1%). Clinical activity seen with the olaparib regimens was particularly notable in patients harboring germline BRCA mutations^.2

Based on these data, investigators assessed the effect of these all-oral, non-platinum regimens on OS in this population, which was a preplanned, non-analytical end point.

A total of 565 patients were enrolled onto the study. Of these, 187 were on the chemotherapy arm, 189 received the olaparib combination, and 189 received olaparib monotherapy.

The majority of patients across the 3 arms had an ECOG performance status of 0 (78.1% with chemotherapy; 73.5% with combination; 76.2% with olaparib), were White (87.7%; 86.2%; 85.2%), had serous histology (93.6%; 92.6%; 97.4%), and had not received prior angiogenic therapy (92.0%; 91.0%; 91.5%). Additionally, most patients had received 1 prior line of therapy (66.8%; 64.6%; 64.6%) followed by 2 prior lines (24.6%; 28.6%; 28.0%) and 3 or more lines (8.6%; 6.9%; 7.4%).

Germline BRCA mutations were observed in 23.5%, 23.8%, and 23.8% of patients in the chemotherapy, olaparib combination, and olaparib monotherapy arms, respectively. The percentage of patients with a PFI of over 12 months was 49.2% in the chemotherapy arm, 50.3% in the combination arm, and 49.7% in the monotherapy arm. Corresponding percentages for patients with a PFI of 6 to 12 months were 50.8%, 47.9%, and 50.3%.

The final OS analysis was conducted upon the occurrence of at least 265 deaths among participants assigned to either the chemotherapy arm or the combination arm. The study aimed for approximately 80% power, assuming proportional hazards, to detect a 30% reduction in the hazard of death (HR, 0.70), with a type I error set to 0.025 for a one-tailed test. Since the PFS end point was not met, a formal interpretation of OS analyses was not conducted. Data collection ended on March 7, 2023, after 266 events were reported in these 2 treatment arms.

Among all enrolled patients, a total of 419 deaths were reported. Sixty patients were still alive by the time of data analysis. In the chemotherapy arm, 27.3% of patients withdrew from the study, including 6 patients who withdrew after disease progression. Withdrawals also occurred in 7.9% of patients in the combination arm and 10.6% of those in the monotherapy arm, with 7 and 5 withdrawals occurring after progression in these respective arms.

Data from the updated analysis of PFS according to BRCA mutational status showed that patients with BRCA1/2 mutations experienced a median OS of 10.5 months with chemotherapy, 18.0 months with olaparib plus cediranib (HR, 0.56; 95% CI, 0.33-0.95), and 12.7 months with olaparib monotherapy (HR, 0.65; 95% CI, 0.39-1.09). In the BRCA1/2 wild-type population, the median PFS was 9.7 months, 8.9 months, and 6.6 months, and 8.9 months for the chemotherapy, combination (HR, 0.98; 95% CI, 0.74-1.30), and monotherapy (HR, 1.39; 95% CI, 1.05-1.84) arms, respectively.

The overall incidence of therapy-related myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) in the study was low. A total of 5 events were observed, including 3 MDS events and 2 AML events. Both AML events occurred in patients treated with cediranib plus olaparib. Two MDS events occurred with the olaparib combination, and 1 event occurred with carboplatin plus paclitaxel. Notably, 1 patient harboring a BRCA mutation was diagnosed with an MDS event while being treated with cediranib plus olaparib. The remaining 4 patients did not experience an MDS/AML event on study treatment.

Investigators noted that caution should be exhibited when interpreting results, as a high proportion of patients withdrew early from survival follow-up, particularly in the control arm.

“These results are also confounded by the number of patients who crossed over to receive a PARP inhibitor at some point on the SOC arm…we are looking at the additional crossover events,” Liu concluded.

References

1. Liu JF, Brady M, Matulonis UA, et al. Overall survival outcomes from NRG-GY004, a phase III study comparing single-agent olaparib or combination cediranib and olaparib to platinum based chemotherapy in recurrent platinum sensitive ovarian cancer. Ann Oncol. 2023;34(suppl 2):S1285. doi:10.1016/j.annonc.2023.10.039
2. Liu JF, Brady MF, Matulonis UA, et al. Olaparib with or without cediranib versus platinum-based chemotherapy in recurrent platinum-sensitive ovarian cancer (NRG-GY004): a randomized, open-label, phase III trial. J Clin Oncol. 2022;40(19):2138-2147. doi:10.1200/JCO.21.02011