Novel targeted treatment strategies and new trial endpoints in recurrent, platinum-sensitive ovarian cancer were highlighted in a gynecologic cancer session at the Best of ASCO New Orleans. At the meeting, Karen McLean, MD, PhD, of the University of Michigan Medical Center, Ann Arbor, presented this year’s top selected abstracts from the 2017 ASCO Annual Meeting in Chicago.¹ 

Dr. McLean presented updated overall survival data from the ICON6 trial of the investigational vascular endothelial growth factor (VEGF) inhibitor cediranib in relapsed ovarian cancer. She also discussed health-related quality of life and patient-centered outcomes in ovarian cancer patients from the SOLO-2 trial, in which maintenance therapy with the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib (Lynparza) after chemotherapy resulted in a statistically significant improvement in progression-free survival. 

ICON6 Outcomes With Cediranib 

Primary analysis of the double-blind, placebo-controlled phase III ICON6 trial was previously reported in The Lancet by Ledermann et al.² The study showed a significant 2.3-month extension in progression-free survival using cediranib with chemotherapy and as maintenance, compared to chemotherapy and placebo in platinum-sensitive relapsed ovarian cancer. At the 2017 ASCO Annual Meeting, the investigators presented updated overall survival results from the trial.³ 

Toxicity is an important ­consideration in cancer ­therapy, particularly in the recurrent and maintenance therapy ­settings, where cumulative ­toxicity comes into play.

— Karen McLean, MD, PhD

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Cediranib is a potent oral antiangiogenic agent that has demonstrated antitumor activity in recurrent ovarian cancer. ICON6 enrolled patients with platinum-sensitive recurrent disease and was originally designed to recruit 2,000 patients to assess efficacy. Its primary endpoint was overall survival, but due to disappointing outcomes with cediranib in pivotal trials of other cancer types, the manufacturer discontinued cediranib development in September 2011, leading to an unplanned redesign of the study. 

The sample size was reduced to 456 patients, progression-free survival became the primary outcome, and the investigators focused on arms A and C, comparing chemotherapy and placebo (n = 118) to cediranib given concurrently with chemotherapy and as maintenance therapy (n = 164), respectively. In arm B, cediranib was given with chemotherapy followed by placebo as maintenance (n = 174). 

Progression-free survival results first published in The Lancet did demonstrate a statistically significant 2.3-month improvement with cediranib. But the difference was modest, due to high rates of toxicity leading to treatment discontinuation: 39% in arm C, compared to 12% in arm A, noted Dr. McLean. In their ASCO Annual Meeting presentation, the investigators reported no statistically significant difference in overall survival (19.9 months in arm A vs 27.3 months in arm C; hazard ratio = 0.85). 

Restricted Mean Survival Time Shows Benefit

According to Dr. McLean, the authors carried out an additional preplanned statistical analysis to assess for improved overall survival with the addition of cediranib therapy. “They argued that hazard ratio is not the best way to look at these data, because they find the hazard ratio is not proportional over time in their patient population,” she explained. “They instead showed a restricted mean survival time to describe the size of the treatment effect,” she continued. An evaluation of mean survival instead of median survival shows approximately a 5-month difference in overall survival with ceridanib (34.2 vs 29.4 months), though this is not the most common way we compare treatment group outcomes, she noted.

Eighty-one percent of patients in the study had a third line of treatment, and 58% received a fourth line, and for patients receiving cediranib, the time to next therapy was longer (13.2 months in arm C vs 10.7 months in arm A). “The investigators carried out a number of survival analyses over the course of this study. Throughout, median survival was longer with concurrent and maintenance cediranib but did not reach statistical significance at any of these time points,” said Dr. McLean. 

Clear evidence that cediranib extends progression-free survival exists, the authors concluded, and the consistent trend in favor of an overall survival benefit suggests a potential future for cediranib. They did, however, recognize that the revised design of ICON6 was unavoidably underpowered for survival, with a median difference in overall survival of 7.4 months that did not reach statistical significance. 

The maintenance strategy with cediranib is being explored further in ICON9, which will evaluate the addition of cediranib to olaparib maintenance following platinum-based therapy for first platinum-sensitive relapse in BRCA-mutated and BRCA–wild-type high-grade ovarian cancers.

“This is an interesting area of study,” Dr. McLean said. “ICON9 explores the combination of cediranib with a PARP inhibitor. Data suggest that antivascular therapy affects BRCA function, so maybe an antivascular agent would improve sensitivity to PARP inhibitors.” 

According to Dr. McLean, the findings from ICON6 are consistent with other work involving antiangiogenic agents in ovarian cancer. Multiple studies have shown statistically significant improvements in progression-free survival in this setting, ranging from approximately 2 to 5 months, but no improvement in overall survival. “I think we’re still trying to determine when antiangiogenic therapies are appropriate in ovarian cancer,” she said. “And I don’t think these decisions can be made without considering the issues of toxicity and cost.” 

Olaparib Findings in SOLO-2 

In the SOLO-2 phase III trial⁴ of patients with germline BRCA-mutated platinum-sensitive relapsed serous ovarian cancer, maintenance olaparib given after response to chemotherapy (n = 196) resulted in a 13.6-month improvement in progression-free survival vs placebo (n = 99), with a hazard ratio of 0.30 (P < .0001). But the investigators’ a priori hypothesis, presented at the 2017 ASCO Annual Meeting, stated that maintenance therapy with olaparib would not negatively impact health-related quality of life compared to placebo and would be associated with additional patient-centered benefits to support the prolongation of progression-free survival.⁵ 

With regard to maintenance therapy, they argued that progression-free survival does not take into account patients’ health-related quality of life while on treatment. Toxicity of treatment should be acceptable, with limited impact on health-related quality of life, and delay in disease progression should also be associated with a longer duration of “good” quality of life for patients. 

Health-related quality of life was evaluated by the Functional Assessment of Cancer Therapy–Ovarian Trial Outcome Index (FACT-O TOI), and the change from baseline over 12 months of therapy was measured in all 295 patients. As the investigators hypothesized, there was no significant detrimental effect of olaparib on health-related quality of life compared to placebo (change from baseline in TOI score was –3.1 for olaparib and –2.9 for placebo). Maintenance olaparib also resulted in a longer time until first and second subsequent therapies compared to placebo. 

Additionally, the significant improvement in progression-free survival with olaparib was associated with secondary patient-centered benefits, including 6.3 months longer without symptoms of disease or treatment toxicity and 6.7 months longer quality-adjusted progression-free survival (a combination of quality-of-life and progression-free survival variables). While there was some initial toxicity with olaparib vs placebo, significant patient-centered benefits support the use of olaparib, according to Dr. McLean. 

At the ASCO Annual Meeting, the team of investigators highlighted patient-centered outcomes as important trial endpoints that show a statistically significant benefit for patients receiving PARP inhibitor therapy. Dr. McLean corroborated these findings at Best of ASCO and stressed that all patients with ovarian cancer should undergo genetic testing. 

She added that a major theme in gynecology at the Annual Meeting was the question of efficacy vs toxicity. “Toxicity is an important consideration in cancer therapy, particularly in the recurrent and maintenance therapy settings, where cumulative toxicity comes into play,” she said. ■

DISCLOSURE: Dr. McLean reported no conflicts of interest.

REFERENCES

1. McLean K: Gynecologic cancer. Best of ASCO New Orleans. Presented July 29, 2017.

2. Ledermann JA, Embleton AC, Raja F, et al: Cediranib in patients with relapsed platinum-sensitive ovarian cancer (ICON6): A randomized, double-blind, placebo-controlled phase 3 trial. Lancet 387:1066-1074, 2016.

3. Ledermann JA, Embleton AC, Perren T, et al: Overall survival results of ICON6: A trial of chemotherapy and cediranib in relapsed ovarian cancer. 2017 ASCO Annual Meeting. Abstract 5506. Presented June 2, 2017.

4. Pujade-Lauraine E, Ledermann JA, Selle F, et al: Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): A double-blind, randomized, placebo-controlled, phase 3 trial. Lancet Oncol. July 25, 2017 (early release online).

5. Friedlander M, Gebski V, Gibbs E, et al: Health-related quality of life and patient-centered outcomes with maintenance olaparib compared with placebo following chemotherapy in patients with germline BRCA-mutated platinum-sensitive relapsed serous ovarian cancer: SOLO2 phase III trial. 2017 ASCO Annual Meeting. Abstract 5507. Presented June 2, 2017.