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
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.
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.
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.The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.