Prognostic analysis of single-agent olaparib or combination cediranib and olaparib for platinum sensitive recurrent ovarian cancer: overall survival outcomes from NRG-GY004

Background of the study and related research

Ovarian cancer is one of the leading causes of death in women (1). With respect to screening for epithelial ovarian cancer (EOC), identification of genetic mutations involved in increased risk of developing the disease is of primary importance for prevention strategies. Screening with CA125 combined with transvaginal ultrasonography has not shown a clear reduction in mortality, and although the combination of CA125 and human epididymal protein 4 (HE4) has been used in clinical practice, an effective screening method to reduce mortality has not yet been established (2). Although ovarian cancer shows good sensitivity to initial chemotherapy, many cases are already disseminated at the time of diagnosis and have a high probability of recurrence, leading to a poor prognosis (3). Re-administration of platinum-based chemotherapy for platinum-sensitive relapsed ovarian cancer (PSR OC) can be highly effective in many patients, however, repeated administration of platinum agent may result in adverse events that impair the patient’s quality of life, including the development of allergy to platinum agent, prolonged myelosuppression, and severe peripheral neuropathy (4). In order to avoid these adverse events, platinum agents can be continued by switching to a different platinum drug or by performing desensitization therapy to the drug. However, there is currently no established protocol for the steady and safe continuation of platinum therapy in such patients. Therefore, the development of non-platinum treatment options for PSR OC is considered a clinically important issue.

With the development of genomic medicine and molecular targeted drugs, the efficacy of PARP inhibitors (PARPis) and angiogenesis inhibitors for recurrent OC has been demonstrated (5-8), and there are great expectations for new treatment strategies that combine with molecular targeted drugs. PARPis are known to be effective for tumors showing homologous recombination deficiency (HRD), and the drug indication is being considered for expansion to patients who have shown resistance to “platinum-containing chemotherapy” and “PARP inhibitors” in the past. Currently, there are high expectations for combination therapy with cytotoxic anticancer agents including platinum-based drugs, angiogenesis inhibitors, immune checkpoint inhibitors, and DNA damage response modifiers (9). Several studies have suggested that PARPis and angiogenesis inhibitors (Ais) act synergistically in PSR OC (10,11). The mechanism responsible for the synergistic effects is thought to be the downregulation of genes related to homologous recombination in the environment of hypoxic stress induced by angiogenesis inhibitors, resulting in an increase in tumor cells deficient in homologous recombination repair (HRR) mechanisms. In addition, the following preclinical study reported another mechanism (12). In patients treated with olaparib, a PARP inhibitor (PARPi), in combination with cediranib, which is both an angiogenesis and tyrosine kinase inhibitor (TKI), antiplatelet-derived growth factor receptor activity caused by cediranib increased tumor cells with HRD independent of the hypoxic stress environment. Eventually, the sensitivity of tumor cells to PARPis was increased.

Cediranib is an oral TKI of vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, and c-kit. Cediranib has activity in recurrent EOC, tubal cancer, and peritoneal cancer with predictable toxicities observed with other TKIs. Adverse events with cediranib essentially do not overlap with those with PARPis (13). In 2014, the results of a phase II study showed that the combination of cediranib and olaparib significantly prolonged progression-free survival (PFS) by 8.7 months compared to olaparib monotherapy in PSR OC patients (14). Furthermore, an additional analysis of the above phase II study was reported in 2019. Combination therapy of cediranib and olaparib also demonstrated significantly prolonged PFS and overall survival (OS) for PSR OC patients without germline BRCA mutation (gBRCAm) compared to olaparib monotherapy (15).

Progress of this research

NRG-GY004 is an open-label, randomized, phase III trial conducted in the United States and Canada (16). Eligible patients had high-grade serous or endometrioid PSR OC. Patients were randomly assigned 1:1:1 to SOC (carboplatin/paclitaxel; carboplatin/gemcitabine; or carboplatin/liposomal doxorubicin), O (300 mg twice daily), or C + O (C 30 mg daily + O 200 mg twice daily), stratified by gBRCAm status, platinum-free interval (PFI) (6–12 vs. >12 months), and prior anti-angiogenic therapy. The primary endpoint was PFS in the intention-to-treat population. Secondary endpoints included activity within germline BRCA-mutated or wild-type subgroups and patient-reported outcomes (PROs).

The primary analysis analyzed the activity of two all-oral nonplatinum alternatives, olaparib or olaparib/cediranib, vs. platinum-based chemotherapy (17). Combination of olaparib/cediranib did not improve PFS compared with chemotherapy and resulted in reduced PROs. Notably, in patients with a gBRCAm, both olaparib and olaparib/cediranib had significant clinical activity.

Outline of this presentation

This presentation was a report of an OS analysis, which was pre-set in NRG-GY004. OS was a secondary endpoint; analysis was specified to occur when at least 265 events had occurred cumulatively in the SOC and C + O arms. As a result, 528 patients (166 SOC, 183 O, 179 C + O) were analyzed in this OS analysis and 23.7% of patients had gBRCAm. The hazard ratio (HR) for OS was 1.27 (95% CI: 0.99–1.62, P=0.06) for O vs. SOC and 1.12 (95% CI: 0.87–1.43, P=0.38) for C + O vs. SOC, with median OS of 32.7, 31.0, and 33.5 months for SOC, O, and C + O, respectively.

Stratified analysis by gBRCAm status also showed no significant prolongation of OS in patients with or without gBRCAm in the O and C + O groups compared to the SOC group. Forty-six cases on SOC had nonprotocol therapy before disease progression, including 36 cases receiving PARPi. 27.3% of cases on SOC, 7.9% on O, and 10.6% on C + O terminated OS follow-up early prior to death. In conclusion, neither O nor C + O improved OS compared to SOC as treatment for PSR OC.

Significance and limitation of this study

The significance of this study is to propose a non-platinum regimen as a new treatment option for PSR OC patients. Offering a non-platinum regimen that is as effective as a platinum regimen to PSR OC patients would be a great benefit to patients who are unable to continue a platinum regimen due to hypersensitivity reactions or prolonged myelosuppression caused by repeated administration of platinum-based chemotherapy. Furthermore, since platinum-based chemotherapy essentially requires intravenous administration every 3 weeks, cediranib/olaparib therapy, which can be administered orally, has advantages in maintaining patient quality of life and adherence to anticancer drugs. The phase II/III randomized controlled trials (RCTs) of combination therapy with PARPis and angiogenesis inhibitors reported to date are summarized in Table 1. A subset analysis of NRG-GY004 showed that the cediranib/olaparib combination therapy produced a significant prolongation of OS in patients with non-gBRCAm (15). However, in the present analysis, no OS prolongation was observed in the same group.

The problem with the study design in this presentation is that first, off-protocol treatment (PARPi in 36 patients) was allowed before disease progression was confirmed in the SOC group (46/187 patients). This off-protocol treatment may have led to overestimation of OS and PFS in the SOC group without accurate evaluation. Second, OS may be underestimated in the SOC, O, and C + O treatment groups because some cases have completed OS follow-up before confirming that the patient died. Third, patients with a PFI of 6–12 months, defined as “partially sensitive”, are likely to be included. This would include patients who received platinum-based chemotherapy plus an AI such as bevacizumab or maintenance therapy with a PARPi. There is some debate as to whether these cases can truly be considered platinum-sensitive, and the possibility of patient background bias cannot be ruled out. Although HRD testing in tumor tissue, as in the QUADRA trial (18), could directly examine the biological characteristics of each cancer, gBRCAm status may not reflect the characteristics of recurrent tumors. Fourth, although the eligibility criteria in NRG-GY004 include “evaluable disease”, the comparison of backgrounds in the three groups does not include any mention of the size of the recurrent “evaluable lesions”.

Future development

From a statistical perspective, to assess OS and PFS as accurately as possible, consideration should be given to not allowing crossover, even in RCTs of recurrent ovarian cancer (19,20). RCTs that do not allow crossover are important to clearly assess the efficacy of a particular treatment, however, they are likely to be ethically problematic for participants in clinical trials because they limit their access to other treatment options for a better prognosis.

Although the NRG-GY004 study employed gBRCAm status as an indicator of PARPi sensitivity in its stratified analysis, biomarkers that predict cediranib sensitivity should also be discussed. In general, biomarkers that may be relevant to predict the efficacy of AIs such as cediranib include genetic mutations involving the VEGF pathway (21,22), tumor microenvironment factors (23), and circulating biomarkers (24). Evaluation of these biomarkers may lead to the identification of patients who will respond to cediranib. Whole genome sequencing may also identify a number of genetic variants associated with HRD, which may allow for more accurate prediction of susceptibility to PARPis (25).

Combination therapy with PARPi and AI also has the potential to be a strategy to overcome drug resistance by synergistically enhancing antitumor activity against ovarian cancer (26). In addition to AIs and immune checkpoint inhibitors, several other drugs and compounds are known to affect HRD in various cancers, including ovarian cancer (27-30), and we believe that these agents may be candidates for new clinical trials in the future.

Acknowledgments

We would like to thank Mr. Kenshin Sekine and Mr. Taishin Sekine for English editing.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Gynecology and Pelvic Medicine. The article has undergone external peer review.

Peer Review File: Available at https://gpm.amegroups.com/article/view/10.21037/gpm-24-20/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gpm.amegroups.com/article/view/10.21037/gpm-24-20/coif). M.S. serves as an unpaid editorial board member of Gynecology and Pelvic Medicine from March 2023 to February 2025. M.S. received lecture fees from AstraZeneca. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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