Abstract
Background
Olaparib is a poly(ADP-ribose) polymerase inhibitor and cediranib is an oral anti-angiogenic. In the primary analysis of this phase II study, combination cediranib/olaparib improved progression-free survival (PFS) compared with olaparib alone in relapsed platinum-sensitive ovarian cancer. This updated analysis was conducted to characterize overall survival (OS) and update PFS outcomes.
Patients and methods
Ninety patients were enrolled to this randomized, open-label, phase II study between October 2011 and June 2013 across nine United States-based academic centers. Data cut-off was 21 December 2016, with a median follow-up of 46 months. Participants had relapsed platinum-sensitive ovarian cancer of high-grade serous or endometrioid histology or had a deleterious germline BRCA1/2 mutation (gBRCAm). Participants were randomized to receive olaparib capsules 400 mg twice daily or cediranib 30 mg daily and olaparib capsules 200 mg twice daily until disease progression.
Results
In this updated analysis, median PFS remained significantly longer with cediranib/olaparib compared with olaparib alone (16.5 versus 8.2 months, hazard ratio 0.50; P = 0.007). Subset analyses within stratum defined by BRCA status demonstrated statistically significant improvement in PFS (23.7 versus 5.7 months, P = 0.002) and OS (37.8 versus 23.0 months, P = 0.047) in gBRCA wild-type/unknown patients, although OS was not statistically different in the overall study population (44.2 versus 33.3 months, hazard ratio 0.64; P = 0.11). PFS and OS appeared similar between the two arms in gBRCAm patients. The most common CTCAE grade 3/4 adverse events with cediranib/olaparib remained fatigue, diarrhea, and hypertension.
Conclusions
Combination cediranib/olaparib significantly extends PFS compared with olaparib alone in relapsed platinum-sensitive ovarian cancer. Subset analyses suggest this margin of benefit is driven by PFS prolongation in patients without gBRCAm. OS was also significantly increased by the cediranib/olaparib combination in this subset of patients. Additional studies of this combination are ongoing and should incorporate analyses based upon BRCA status.
Trial Registration
Clinicaltrials.gov Identifier NCT0111648
Keywords: ovarian cancer, antiangiogenic therapies, PARP inhibitors, combination targeted therapies
Key Message
In this updated analysis, combination cediranib/olaparib significantly improved progression-free survival over olaparib (16.5 versus 8.2 months) in relapsed platinum-sensitive ovarian cancer and also improved overall survival in those women without a germline BRCA mutation (37.8 versus 23.0 months, P = 0.047), although the difference in overall survival (44.2 versus 33.3 months) was not statistically significant in the overall study population.
Introduction
Ovarian cancer remains the fifth leading cause of cancer death among women in the United States and the leading cause of death from gynecologic malignancy [1]. While platinum-based therapy remains the standard of care for women with platinum-sensitive recurrence, repeated exposure to platinum can cause increased toxicity or risk of hypersensitivity reactions. New therapeutic options in this setting would therefore be of clinical interest.
Poly(ADP-ribose) polymerase (PARP) inhibitors have emerged as a promising drug class for women with recurrent ovarian cancer in a number of settings, including for treatment of BRCA mutation–related relapsed disease or as maintenance therapy in the platinum sensitive setting following response to platinum-based therapy [2–7]. Similarly, clinical experience with antiangiogenics in ovarian cancer continues to grow, with bevacizumab together with platinum-based chemotherapy and subsequent maintenance in the platinum sensitive relapsed setting now approved by regulatory agencies in both the United States and the European Union [8, 9].
The combination of antiangiogenic agents together with PARP inhibitors is an area of developing interest in ovarian cancer. Preclinical studies demonstrate that antiangiogenic agents can induce a hypoxic environment, resulting in down-regulation of genes of homologous recombination (HR) [10–13]. This induction of an HR-deficient state in cells that would otherwise be HR-proficient could lead to an induced vulnerability to drugs such as PARP inhibitors, resulting in synergistic activity between these two classes of drugs [14].
Previously, we had reported on the outcomes of a randomized, open-label, phase II study comparing the combination of the antiangiogenic tyrosine kinase inhibitor cediranib together with the PARP inhibitor olaparib to olaparib alone in women with relapsed platinum sensitive high-grade serous or endometrioid ovarian, fallopian tube or primary peritoneal cancer [15]. Women participating in this study were randomized 1 : 1 to receive either the combination of cediranib at 30 mg daily together with olaparib capsules 200 mg twice daily or olaparib monotherapy with olaparib capsules 400 mg twice daily. Treatment was continued until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS) in the intention to treat population, and the primary analysis was carried out after 47 events had occurred. At that time, median PFS was found to be 17.7 months for women in the cediranib plus olaparib arm of the study compared with 9.0 months for women in the olaparib monotherapy arm [hazard ratio 0.42, 95% confidence interval (95% CI) 0.23–0.76; P = 0.005]. Grade 3 and 4 adverse events (AEs) were more common in women receiving combination therapy.
We now report the updated PFS results, overall survival (OS) results, and updated safety data from the trial.
Methods
Patients and study design
The patient eligibility criteria and study design for this trial (NCT01116648) have previously been described [15]. In brief, all patients had relapsed high-grade serous or high-grade endometrioid ovarian cancer or a high-grade histology with a known germline BRCA mutation (gBRCAm); platinum-sensitive disease, defined as disease recurrence more than 6 months after last receipt of platinum with no history of progression on platinum; and measurable disease per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. Patients could have received prior antiangiogenic agents only in the first-line setting and were excluded if they had previously received a PARP inhibitor. Additional exclusion criteria included uncontrolled hypertension, history of hypertensive crisis, abdominal fistula or perforation, bowel obstruction within the prior 3 months, or major surgical procedure within the prior 28 days.
Patients were randomized 1 : 1 to receive either cediranib and olaparib or olaparib alone, with germline BRCA mutation status (mutated versus wild type versus unknown) and receipt of prior antiangiogenic therapy as stratification factors. Patients continued on study therapy until progression by RECIST 1.1 criteria or unacceptable toxicity. Restaging studies occurred every 8 weeks. Patients were followed up for 3 years after discontinuation from study treatment or until death, whichever occurred first.
Study end points and statistical analysis
Study end points and statistical methods for this update analysis are consistent with the primary analysis [15]. In brief, PFS was defined as time from randomization to investigator-assessed radiographic progression by RECIST 1.1 criteria or death. Patients alive without evidence of progression were censored at the last disease assessment. OS was defined as time from randomization to death, censoring at time of last patient contact. AEs were graded by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Time-to-event end points were summarized by treatment arm and within patient subgroups using Kaplan–Meier estimates. Hazard ratios were reported from Cox proportional hazard models with stratum defined by germline BRCA status and prior antiangiogenic therapy, and P-values were reported from Score (logrank) tests. All analyses were conducted in an intent-to-treat manner with study arms defined according to randomized treatment assignment.
Of note, this randomized phase II trial was not designed to conduct an analysis of OS in a time- or event-driven manner that controls Type II error (power). For the primary analysis, the target accrual of 90 patients was set to have 86% power to detect an improvement in median PFS from 6 to 10.5 months (hazard ratio = 0.57) when using a one-sided alpha = 0.1. Here, secondary analyses are conducted using a nominal two-sided alpha = 0.05. For a two-sample comparison of time-to-event end points, this provides 80% power to detect hazard ratios of 0.43, 0.47, and 0.50 with 50, 60, and 70 events, respectively (PASS 15; Kaysville, UT). Statistical analyses were carried out using SAS v9.2 (Cary, NC) and R v3.4.4.
Results
Patient characteristics
Between October 2011 and June 2013, 90 patients were enrolled across nine treatment centers in the United States, with 44 patients randomly allocated to receive cediranib and olaparib combination therapy and 46 randomized to receive olaparib alone (Figure 1). As previously reported, baseline patient characteristics were generally balanced across both groups. Forty-seven women were known to be gBRCAm based upon available clinical testing results.
Figure 1.
Updated CONSORT diagram. PFS, progression-free survival.
Updated PFS results and final OS analysis
At the time of data cut off on 21 December 2016, seven patients remained on therapy, with four patients on combination cediranib/olaparib and three patients receiving olaparib alone. Duration for those still on therapy ranged from 45 to 61 months. With a median follow-up of 46 months [16], a total of 67 patients (74%) had experienced a PFS event. The updated PFS was 16.5 months in the cediranib and olaparib combination arm versus 8.2 months in the olaparib monotherapy arm (hazard ratio 0.50, 95% CI 0.30–0.83, P = 0.006) (Figure 2A).
Figure 2.
Kaplan–Meier curves of (A) updated progression-free survival by the treatment arm and (B) overall survival by the treatment arm.
It had been previously reported that OS at 24 months was 65% in the olaparib arm and 81% in the cediranib plus olaparib arm, but a formal comparison had not been made due to an insufficient number of events. At the time of this analysis, a total of 52 patients (58%) had died. Median OS was 44.2 months in the cediranib and olaparib combination arm compared with 33.3 months in the olaparib monotherapy arm (hazard ratio 0.64, 95% CI 0.36–1.11, P = 0.11) (Figure 2B).
Exploratory analyses by germline BRCA status
Post-hoc exploratory analyses of the updated PFS as well as OS were again conducted in the subsets of patients who were gBRCAm (47 patients) and those who were germline BRCA wild-type or whose BRCA status was unknown (gBRCAwt/unknown; 43 patients). In women who were gBRCAm, there was no significant difference in PFS between patients receiving combination cediranib/olaparib and those receiving olaparib alone (16.4 versus 16.5 months, hazard ratio 0.76, 95% CI 0.38–1.49, P = 0.42). Similarly, OS between the two arms for women who were gBRCAm did not differ substantially (44.2 versus 40.1 months, hazard ratio 0.86, 95% CI 0.41–1.82, P = 0.70) (Figure 3A).
Figure 3.
Kaplan–Meier curves of updated progression-free survival and overall survival in (A) germline BRCA-mutated patients and (B) germline BRCA wild-type/unknown patients.
PFS was significantly improved between those patients receiving combination cediranib/olaparib compared with olaparib alone (23.7 versus 5.7 months, hazard ratio 0.31, 95% CI 0.15–0.66, P = 0.0013) in the subset of women who were gBRCAwt/unknown. Moreover, OS was substantially improved in this subset of patients (37.8 versus 23.0 months), with this improvement reaching a nominal level of statistical significance (hazard ratio 0.44, 95% CI 0.19–1.01, P = 0.047) (Figure 3B). These data demonstrate that the improvements in OS with cediranib/olaparib are consistent with the findings with PFS, within and across subgroups defined by germline BRCA status.
Safety
After a cumulative exposure of 69.9 patient-years in the cediranib/olaparib arm and 45.3 patient-years in the olaparib arm, updated safety data confirmed that drug-related AEs are more common in the combination arm (478 events among 44 subjects) compared with olaparib alone (180 events reported among 46 subjects). Table 1 demonstrates the treatment-related AEs occurring in at least 10% of patients on either arm of the study. The most common grade 3 or higher AEs occurring in the combination arm continued to be diarrhea, fatigue, and hypertension. Two grade 4 events were previously reported in the cediranib/olaparib arm (one hypertensive crisis and one myelodysplastic syndrome). No new grade 4 events were noted during this updated safety analysis.
Table 1.
Treatment-related adverse events occurring in at least 10% of patients on either arm of therapy
| Category of toxicity | Toxicity | Treatment arm |
Total |
||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Olaparib (N = 46) |
Cediranib/olaparib (N = 44) |
||||||||||||||||
| Maximum grade |
Maximum grade |
||||||||||||||||
| 1–2 |
3 |
4 |
1–2 |
3 |
4 |
Olaparib (N = 46) |
Cediranib/olaparib (N = 44) |
||||||||||
| N | % | N | % | N | % | N | % | N | % | N | % | N | % | N | % | ||
| Blood and lymphatic system disorders | Anemia | 7 | 15.2 | 1 | 2.2 | – | – | 7 | 15.9 | – | – | – | – | 8 | 17.4 | 7 | 15.9 |
| Endocrine disorders | Hypothyroidism | 1 | 2.2 | – | – | – | – | 7 | 15.9 | – | – | – | – | 1 | 2.2 | 7 | 15.9 |
| Gastrointestinal disorders | Abdominal pain | 3 | 6.5 | – | – | – | – | 7 | 15.9 | 2 | 4.5 | – | – | 3 | 6.5 | 9 | 20.5 |
| Constipation | 2 | 4.3 | – | – | – | – | 8 | 18.2 | – | – | – | – | 2 | 4.3 | 8 | 18.2 | |
| Diarrhea | 1 | 2.2 | – | – | – | – | 30 | 68.2 | 11 | 25.0 | – | – | 1 | 2.2 | 41 | 93.2 | |
| Dry mouth | – | – | – | – | – | – | 6 | 13.6 | – | – | – | – | – | – | 6 | 13.6 | |
| Dyspepsia | 9 | 19.6 | – | – | – | – | 7 | 15.9 | – | – | – | – | 9 | 19.6 | 7 | 15.9 | |
| Gastroesophageal reflux disease | 2 | 4.3 | – | – | – | – | 5 | 11.4 | – | – | – | – | 2 | 4.3 | 5 | 11.4 | |
| Gastrointestinal disorders— Other, specify | – | – | – | – | – | – | 7 | 15.9 | – | – | – | – | – | – | 7 | 15.9 | |
| Mucositis oral | – | – | – | – | – | – | 9 | 20.5 | – | – | – | – | – | – | 9 | 20.5 | |
| Nausea | 34 | 73.9 | – | – | – | – | 30 | 68.2 | 2 | 4.5 | – | – | 34 | 73.9 | 32 | 72.7 | |
| Vomiting | 8 | 17.4 | – | – | – | – | 8 | 18.2 | 1 | 2.3 | – | – | 8 | 17.4 | 9 | 20.5 | |
| General disorders and admin site conditions | Fatigue | 21 | 45.7 | 5 | 10.9 | – | – | 23 | 52.3 | 12 | 27.3 | – | – | 26 | 56.5 | 35 | 79.5 |
| Investigations | Creatinine increased | 3 | 6.5 | – | – | – | – | 6 | 13.6 | – | – | – | – | 3 | 6.5 | 6 | 13.6 |
| Neutrophil count decreased | 5 | 10.9 | – | – | – | – | 4 | 9.1 | – | – | – | – | 5 | 10.9 | 4 | 9.1 | |
| Platelet count decreased | 3 | 6.5 | – | – | – | – | 8 | 18.2 | – | – | – | – | 3 | 6.5 | 8 | 18.2 | |
| Weight loss | – | – | – | – | – | – | 10 | 22.7 | – | – | – | – | – | – | 10 | 22.7 | |
| White blood cell decreased | 5 | 10.9 | – | – | – | – | 7 | 15.9 | – | – | – | – | 5 | 10.9 | 7 | 15.9 | |
| Metabolism and nutrition disorders | Anorexia | 4 | 8.7 | – | – | – | – | 13 | 29.5 | – | – | – | – | 4 | 8.7 | 13 | 29.5 |
| Hyponatremia | 1 | 2.2 | – | – | – | – | 5 | 11.4 | – | – | – | – | 1 | 2.2 | 5 | 11.4 | |
| Musculoskeletal and connective tissue disorders | Musculoskeletal and connective tissue disorder—Other, specify | – | – | – | – | – | – | 5 | 11.4 | – | – | – | – | – | – | 5 | 11.4 |
| Myalgia | 2 | 4.3 | – | – | – | – | 5 | 11.4 | – | – | – | – | 2 | 4.3 | 5 | 11.4 | |
| Nervous system disorders | Dizziness | 5 | 10.9 | – | – | – | – | 6 | 13.6 | – | – | – | – | 5 | 10.9 | 6 | 13.6 |
| Dysgeusia | 5 | 10.9 | – | – | – | – | 6 | 13.6 | – | – | – | – | 5 | 10.9 | 6 | 13.6 | |
| Headache | 4 | 8.7 | – | – | – | – | 17 | 38.6 | 3 | 6.8 | – | – | 4 | 8.7 | 20 | 45.5 | |
| Renal and urinary disorders | Proteinuria | – | – | – | – | – | – | 5 | 11.4 | – | – | – | – | – | – | 5 | 11.4 |
| Respiratory, thoracic and mediastinal disorders | Dyspnea | – | – | – | – | – | – | 5 | 11.4 | 1 | 2.3 | – | – | – | – | 6 | 13.6 |
| Epistaxis | – | – | – | – | – | – | 7 | 15.9 | – | – | – | – | – | – | 7 | 15.9 | |
| Hoarseness | – | – | – | – | – | – | 12 | 27.3 | – | – | – | – | – | – | 12 | 27.3 | |
| Skin and subcutaneous tissue disorders | Palmar–plantar erythrodysesthesia syndrome | 1 | 2.2 | – | – | – | – | 8 | 18.2 | – | – | – | – | 1 | 2.2 | 8 | 18.2 |
| Vascular disorders | Hypertension | – | – | – | – | – | – | 16 | 36.4 | 16 | 36.4 | 2 | 4.5 | – | – | 34 | 77.3 |
Discussion
This mature analysis confirms the preliminary findings of improved PFS and a trend for improved OS with the combination of cediranib and olaparib compared with olaparib alone. It further confirms the differential benefit of this combination to olaparib alone in women with relapsed platinum sensitive high-grade serous or endometrioid ovarian cancer who do not have a deleterious BRCA mutation, suggesting that the combination of an antiangiogenic and a PARP inhibitor may create a therapeutic vulnerability in this population.
The exploratory analyses in this study within subsets of women defined by the presence or absence of a germline BRCA mutation suggest that the effect of the combination differs in these patient populations. In the initial study analysis, there was a small degree of difference in PFS in women with a gBRCAm. This difference was not statistically significant and was markedly less than the PFS difference seen between combination cediranib/olaparib and olaparib alone in women who were gBRCAwt/unknown. The updated analysis confirms the initial observations in these two cohorts of patients, with minimal PFS difference now seen in the gBRCAm patients, but continued marked improvement in PFS with the cediranib/olaparib combination for those women who were gBRCAwt/unknown. Of note, a statistically significant improvement in OS with cediranib/olaparib was observed in women who were gBRCAwt/unknown, even though there was minimal difference in OS in the gBRCAm patients and the OS difference in the overall study population did not reach statistical significance.
These observations are of particular interest given hypotheses regarding how cediranib and olaparib or other antiangiogenic/PARP inhibitor combinations might synergize. Preclinical studies have described down-regulation of genes of HR in the setting of hypoxia [10–13], potentially rendering cells more vulnerable to the effects of an agent such as a PARP inhibitor. In correlative studies performed in 13 participants of this study, induction of circulating endothelial cells correlated with increased PFS, supporting the notion that an increase in hypoxia prolonged PFS in these patients [17]. The findings from these subset analyses must be confirmed; however, it may be that gBRCAwt patients will derive greater benefit from the cediranib/olaparib combination compared with olaparib alone as their tumors do not have the intrinsic loss of HR that typically accompanies a BRCA1 or BRCA2 mutation. Similarly, it may be that gBRCAm patients with platinum sensitive disease, suggesting continued loss of HR, will not derive significant additional benefit by adding an antiangiogenic agent to a PARP inhibitor. Results from the first 12 patients treated on the AVANOVA trial suggest activity of combination bevacizumab/niraparib in patients both with and without BRCA mutations [18]. Other PARP inhibitor/antiangiogenic combinations currently under investigation include olaparib and bevacizumab following upfront therapy for newly diagnosed disease (PAOLA-1), rucaparib and bevacizumab in advanced ovarian cancer (MITO25), and niraparib and bevacizumab maintenance following upfront therapy for newly diagnosed disease (OVARIO) [19–21].
The observations from the study are limited by its relatively small size of 90 patients and conduct across only nine academic centers. As previously observed, the combination of cediranib and olaparib is accompanied by characteristic side-effects, including hypertension and diarrhea, that require close management [15, 22]. Prior studies of cediranib together with chemotherapy have resulted in high discontinuation rates of cediranib, up to 39%, in the setting of AEs [23]. In this study, the discontinuation rate for non-progression events was markedly lower (6.8%) despite a 68% rate of grade 3 or higher AEs. This low discontinuation rate was likely due to close monitoring and communication between study teams, the small number of treatment centers involved in the study, and increased experience with AE management among these treatment centers, many of which had participated in the phase I trial of cediranib and olaparib or had prior experience with cediranib in other study settings.
Overall, the results of this updated analysis are consistent with the initial report of the study results. A statistically significant improvement in OS was observed in patients who were gBRCAwt/unknown, although a difference in OS was not observed in the overall study population. Additionally, a continued significant difference in PFS was observed across the whole study population and specifically in those patients who were gBRCAwt/unknown. These data support the ongoing continued development of cediranib and olaparib as well as other antiangiogenic and PARP inhibitor combinations in ovarian cancer; phase II and phase II/III trials of cediranib/olaparib in platinum-sensitive (NRG-GY004) and platinum-resistant (NRG-GY005) relapsed ovarian cancer, respectively, are currently in progress through the NRG cooperative group [24, 25], and a phase III trial (ICON9) assessing combination cediranib/olaparib compared with olaparib alone as maintenance therapy following response to platinum in recurrent ovarian cancer is also now enrolling [26]. These results also suggest that future studies must account for BRCA status or other measures of HR to fully understand which patients derive the greatest benefit from antiangiogenic/PARP inhibitor combination therapies. If confirmed in additional trials, the findings of a differential effect of cediranib/olaparib in BRCA-mutated versus BRCA wild-type patients might suggest further stratification of the therapeutic approach to patient treatment. Recent approvals and anticipated results suggest that, at a minimum, PARP inhibitors are likely to be incorporated in the initial therapy of BRCA-mutated ovarian cancer. The current survival data suggest that it may be useful to examine the most beneficial time to utilize PARP inhibitor combinations in women with BRCA wild-type disease.
Funding
This work was supported by the National Cancer Institute (NCI) at the National Institutes of Health (NIH) [American Recovery and Reinvestment Act grant (3 U01 CA062490-S2)]; the Intramural Program of the Center for Cancer Research, NCI, NIH; and the Division of Cancer Treatment and Diagnosis, NCI, NIH.
Disclosure
JFL reports advisory board participation for AstraZeneca, Tesaro, Mersana, and Clovis and is the institutional PI of industry-sponsored trials from Genentech/Roche, AstraZeneca, Boston Biomedical, Atara Biotherapeutics, Acetylon, Bristol-Myers Squibb, Agenus, CytomX Therapeutics, Regeneron, Tesaro, and Clovis Oncology. WTB reports research support from Pfizer. RJB reports advisory board participation for Mersana and support to the academic institution from Novartis and Cerulean related to work for clinical trials. GFF has received medical writer support from Genentech and is the institutional PI of industry-sponsored trials from Tesaro, Iovance, Corcept, Merck, Abbvie, Syndax, and 47 Inc. BJR reports advisory board participation for AstraZeneca, Tesaro, Clovis, and Genentech. UAM reports consultancy relationships with Merck, Fujifilm, Mersana, Geneos, Immunogen, Clovis, Astrazeneca, Cerulean, Myriad Genetics, and Eli Lilly and has received grant support for an investigator-initiated clinical trial from Merck. All remaining authors have declared no conflicts of interest.
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