As reported in the Journal of Clinical Oncology by Joyce F. Liu, MD, and colleagues, the phase III NRG-GY004 trial has shown no significant improvement in progression-free survival with olaparib/cediranib vs platinum-based chemotherapy in patients with recurrent platinum-sensitive ovarian cancer. Greater activity of olaparib alone and olaparib/cediranib was observed in patients with BRCA-mutated disease.

The investigators noted that data have suggested that poly (ADP-ribose) polymerase (PARP) inhibitors and antiangiogenic agents may act synergistically in platinum-sensitive ovarian cancer, and that the current trial is the first phase III trial to compare an all-oral nonplatinum regimen to platinum-based chemotherapy in this setting.

Joyce F. Liu, MD

Study Details

The open-label trial included 565 eligible women (intention-to-treat [ITT] population) from sites in the United States and Canada with recurrent high-grade serous or endometrioid platinum-sensitive disease. They were randomly assigned 1:1:1 between February 2016 and November 2017 to receive olaparib at 300 mg twice daily (n = 189), olaparib at 200 mg twice daily plus cediranib at 30 mg once daily (n = 189), or investigator choice of chemotherapy (n = 187). Olaparib and olaparib/cediranib were given until disease progression or unacceptable toxicity. Chemotherapy options consisted of carboplatin and pegylated liposomal doxorubicin (n = 89, 48%), carboplatin and gemcitabine (n = 51, 27%), or carboplatin and paclitaxel (n = 47, 25%), with treatment continued as long as deemed appropriate. The primary endpoint was progression-free survival in the ITT population, with olaparib/cediranib vs chemotherapy being tested first in hierarchical testing.

Progression-Free Survival

Median progression-free survival was 10.3 months (95% confidence interval [CI] = 8.7–11.2 months) in the chemotherapy group, 8.2 months (95% CI = 6.6–8.7 months) in the olaparib group, and 10.4 months (95% CI = 8.5–12.5 months) in the olaparib/cediranib group. The hazard ratio for olaparib/cediranib vs chemotherapy was 0.86 (95% CI = 0.66–1.10, P = .077). Due to lack of significance, other comparisons were not formally tested. The hazard ratio for olaparib vs chemotherapy was 1.2 (95% CI = 0.93–1.5).

A total of 24% of patients in each group had deleterious germline BRCA mutations. In a prespecified analysis among these patients, median progression-free survival was 10.5 months (95% CI = 9.0–12.8 months) with chemotherapy, 18.0 months (95% CI = 12.6–22.1 months) with olaparib/cediranib, and 12.7 months (95% CI = 9.3–17.7) months with olaparib. Compared with chemotherapy, hazard ratios were 0.55 (95% CI = 0.32–0.94) for olaparib/cediranib and 0.63 (95% CI = 0.37–1.07) for olaparib. Among patients without a deleterious germline BRCA mutation, hazard ratios vs chemotherapy were 0.97 (95% CI = 0.73–1.30) for olaparib/cediranib and 1.41 (95% CI = 1.07–1.86) for olaparib.

Overall survival data were not mature at the time of analysis. Estimated median overall survival was 31.3 months for chemotherapy, 30.5 months for olaparib/cediranib, and 29.2 months for olaparib.

Adverse Events

Hematologic adverse events occurred more frequently in the chemotherapy group vs the olaparib and olaparib/cediranib groups, including grade 3 or 4 neutrophil count decrease (32% vs 2%–4%) and platelet decrease (15% vs 1%–2%), although frequency of anemia was similar with olaparib (14% vs 15% with olaparib and 6% with olaparib/cediranib). Nonhematologic adverse events were more common with olaparib/cediranib, including grade ≥ 3 hypertension in 32%, fatigue in 18%, and diarrhea in 14%. Peripheral sensory neuropathy of any grade occurred in 34% of the chemotherapy group, 16% of the olaparib group, and 14% of the olaparib/cediranib group.

Among 489 patients evaluable for patient-reported outcomes, those in the olaparib/cediranib group scored, on average, 1.1 points worse on the nine-item NCCN/FACT-Ovarian Cancer Symptom Index Disease Related Symptom-Physical (NFOSI-DRS-P) subscale (97.5% CI = –2.0 to –0.2, P = .0063) vs chemotherapy; no difference on the subscale was observed between olaparib and chemotherapy.

The investigators concluded, “Combination olaparib/cediranib did not improve progression-free survival compared with chemotherapy and resulted in reduced patient-reported outcomes. Notably, in patients with a germline BRCA mutation, both olaparib and olaparib/cediranib had significant clinical activity.”

Dr. Liu, of Dana-Farber Cancer Institute, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by the National Cancer Institute, Canadian Cancer Society, and AstraZeneca. For full disclosures of the study authors, visit ascopubs.org.