A Review of Selected Presentations From the ESMO Virtual Congress 2020
Patient-Reported Outcomes in Patients Receiving Niraparib in the PRIMA/ENGOT-OV26/GOG-3012 Trial
Niraparib is an oral selective inhibitor of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) 1/2. PARP inhibitors induce apoptosis in cancer cells by interfering with DNA repair mechanisms,1 and they have shown promising safety and efficacy in patients with homologous recombination–deficient (HRD) ovarian cancer. The double-blind phase 3 PRIMA trial compared niraparib vs placebo in patients with ovarian, primary perineal, or fallopian tube cancer who had developed either a partial response (PR) or a complete response (CR) after first-line treatment with platinum-based chemotherapy.2 Stratification factors included treatment with neoadjuvant chemotherapy, best response to first-line platinum therapy, and HRD status. Patients were randomly assigned in a 2:1 ratio to receive niraparib or placebo. The dose of niraparib was based on body weight and platelet count. The primary endpoint was progression-free survival (PFS) among patients with HRD-positive tumors and in the overall population. A prespecified interim analysis for overall survival (OS) was conducted at the time of the primary analysis of progression-free survival.
Among the 733 patients who underwent treatment randomization, tumors were HRD-positive in 50.9%.2 Among the patients in this category, the median PFS was 21.9 months in the niraparib group vs 10.4 months in the placebo group (hazard ratio [HR] for disease progression or death, 0.43; 95% CI, 0.31-0.59; P<.001). In the overall population, PFS was 13.8 months vs 8.2 months, respectively (HR, 0.62; 95% CI, 0.50-0.76; P<.001). At the 24-month interim analysis, the rate of OS was 84% in the niraparib arm vs 77% in the placebo arm (HR, 0.70; 95% CI, 0.44-1.11).
Patient-reported outcomes were evaluated as a secondary endpoint.3 These outcomes were collected via 4 instruments: the Functional Assessment of Cancer Therapy–Ovarian Symptom Index (FOSI),4 the European Quality of Life 5-Dimension 5-Level questionnaire (EQ-5D-5L),5 the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (EORTC-QLQ-C30),6 and the EORTC Quality of Life Questionnaire Ovarian Cancer (EORTC-QLQ-OV28) module.7 The
patient-reported outcomes from these questionnaires were obtained at baseline, every 8 weeks through week 56, and then every 12 weeks until study discontinuation. Patients also reported outcomes at the end of treatment and at 4, 8, 12, and 24 weeks after treatment discontinuation. Throughout the study, the rate of patient adherence was high, exceeding 80% across all instruments used to assess patient-reported outcomes (Figure 1).
FOSI is a validated instrument that measures 8 items related to symptoms in response to treatment for ovarian cancer.4 Patients report on the symptoms they have experienced during the prior 7 days on a 5-point Likert scale ranging from 0 to 4. The Health Utility Index (HUI) is a cumulative score that represents overall outcome across the 8 items. The mean FOSI HUI scores were similar in the patients treated with niraparib or placebo (Figure 2). Results from the FOSI questionnaire showed that the percentages of patients with mild or severe symptoms consisting of lack of energy, nausea, vomiting, and cramping were similar in the 2 treatment arms.
The EORTC QLQ-C30 assesses health-related quality of life with 30 questions.6 The instrument was developed to provide a common scale for measuring health outcomes from different interventions. The questionnaire addresses several aspects of functioning (physical, role, social, emotional, and cognitive), as well as parameters such as pain, fatigue, finances, appetite, nausea and vomiting, diarrhea, constipation, sleep, and quality of life. Scores from the EORTC QLQ-C30 were similar in the patients treated with niraparib or placebo. No difference between the 2 groups was observed in overall quality of life, physical function, and levels of fatigue and pain.
The EORTC QLQ-OV28 was developed specifically for patients with ovarian cancer.7 The results from this instrument also showed similar outcomes in patients treated with niraparib or placebo. No differences were noted in the mean number of abdominal/gastrointestinal symptoms or in other side effects associated with chemotherapy. The HUI based on the EQ-5D-5L questionnaire showed no meaningful difference in changes in health from baseline between the 2 treatment arms. Similarly, EQ-5D-5L scores obtained by means of a visual analogue scale revealed no differences between the niraparib and placebo arms. In conclusion, the results obtained with 4 different instruments used to assess health-related quality of life were similar in patients treated with niraparib or placebo.
References
1. Zheng F, Zhang Y, Chen S, Weng X, Rao Y, Fang H. Mechanism and current progress of poly ADP-ribose polymerase (PARP) inhibitors in the treatment of ovarian cancer. Biomed Pharmacother. 2020;123:109661.
2. González-Martín A, Pothuri B, Vergote I, et al; PRIMA/ENGOT-OV26/GOG-3012 Investigators. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2019;381(25):2391-2402.
3. Pothuri B, Han S, Chase D, et al. Patient-reported outcomes in patients receiving niraparib in the PRIMA/ENGOT-OV26/GOG-3012 trial [ESMO abstract 810MO]. Ann Oncol. 2020;31(suppl 4):S612-S613.
4. Beaumont J, Yount S, Lalla D, et al. Validation of the Functional Assessment of Cancer Therapy-Ovarian (FACT-O) Symptom Index (FOSI) in a phase II clinical trial of pertuzumab in patients with advanced ovarian cancer [ASCO abstract 16021]. J Clin Oncol. 2007;25(18 suppl).
5. Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011;20(10):1727-1736.
6. Groenvold M, Klee MC, Sprangers MAG, Aaronson NK. Validation of the EORTC QLQ-C30 quality of life questionnaire through combined qualitative and quantitative assessment of patient-observer agreement. J Clin Epidemiol. 1997;50(4):441-450.
7. Greimel E, Bottomley A, Cull A, et al; EORTC Quality of Life Group and the Quality of Life Unit. An international field study of the reliability and validity of a disease-specific questionnaire module (the QLQ-OV28) in assessing the quality of life of patients with ovarian cancer. Eur J Cancer. 2003;39(10):1402-1408.
Maintenance Olaparib for Patients With Newly Diagnosed, Advanced Ovarian Cancer and a BRCA Mutation: 5-Year Follow-Up From SOLO1
Despite therapeutic advances in the treatment of ovarian cancer, fewer than half of patients with newly diagnosed disease survive for 5 years.1,2 First-line therapy provides the best opportunity to delay disease progression and prolong survival. The phase 3 SOLO1 trial evaluated maintenance therapy with olaparib among patients with newly diagnosed stage III/IV disease (per criteria from the International Federation of Gynecology and Obstetrics).3 The trial enrolled patients with high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube cancer with a germline BRCA mutation. Patients had undergone cytoreductive surgery and had developed a PR or CR after receiving platinum-based chemotherapy. The trial randomly assigned 391 patients in a 2:1 ratio to olaparib (300 mg twice daily) or placebo for 2 years or until disease progression. The primary endpoint was investigator-assessed PFS. After a median follow-up of 41 months, the HR for disease progression or death was 0.30 (95% CI, 0.23-0.41; P<.001).
A long-term follow-up analysis evaluated efficacy and safety among patients in the SOLO1 trial.4 The median follow-up was 4.8 years for the olaparib arm and 5.0 years for the placebo arm. The long-term median PFS was 56.0 months in the olaparib arm vs 13.8 months in the placebo arm (HR, 0.33; 95% CI, 0.25-0.43; Figure 3). The median duration of treatment was 24.6 months vs 13.9 months, respectively. Among patients with a CR after chemotherapy, the median recurrence-free survival was not reached with olaparib vs 15.3 months with placebo (HR, 0.37; 95% CI, 0.27-0.52). In the olaparib arm, 52% of the patients remained recurrence-free at 5 years, compared with 22% in the placebo arm. The secondary outcomes were consistent with a PFS benefit from olaparib. In the overall study population, the median PFS2 (time from randomization to second progression) was not reached with olaparib vs 42.1 months with placebo (HR, 0.46; 95% CI, 0.33-0.65). The median time to the second subsequent therapy was not reached vs 40.7 months, respectively (HR, 0.46; 95% CI, 0.34-0.63). Among patients with a CR at baseline (n=189 in the olaparib arm and n=101 in the placebo arm), the median PFS2 was not reached with olaparib vs 52.9 months with placebo (HR, 0.48; 95% CI, 0.32-0.71), and the median time to second subsequent therapy was not reached vs 47.7 months (HR, 0.35; 95% CI, 0.35-0.72).
The safety profile was consistent with previous reports. More than 90% of patients in each arm experienced an adverse event of any grade. Adverse events of grade 3 or higher were reported in 40% of patients in the olaparib arm vs 19% in the placebo arm, with serious adverse events in 21% vs 13%, respectively. An adverse event led to dose interruption in 52% of the patients receiving maintenance therapy with the PARP inhibitor vs 17% of the patients receiving placebo. No additional cases of myelodysplastic syndrome and/or acute myeloid leukemia emerged.
References
1. Ledermann JA, Raja FA, Fotopoulou C, Gonzalez-Martin A, Colombo N, Sessa C; ESMO Guidelines Working Group. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24(suppl 6):vi24-vi32.
2. Tewari KS, Burger RA, Enserro D, et al. Final overall survival of a randomized trial of bevacizumab for primary treatment of ovarian cancer. J Clin Oncol. 2019;37(26):2317-2328.
3. Moore K, Bookman MA, Sehouli J, et al. Primary results from IMagyn050/GOG 3015/ENGOT-OV39, a double-blind placebo-controlled randomized phase 3 trial of bevacizumab-containing therapy +/– atezolizumab for newly diagnosed stage III/IV ovarian cancer [ESMO abstract LBA31]. Ann Oncol. 2020;31(suppl 4):S1161-S1162.
4. Banerjee S, Moore K, Colombo N, et al. Maintenance olaparib for patients with newly diagnosed, advanced ovarian cancer and a BRCA mutation: 5-year follow-up from SOLO1 [ESMO abstract 811MO]. Ann Oncol. 2020;31(suppl 4):S613.
Individualized Starting Dose of Niraparib in Chinese Patients With Platinum-Sensitive Recurrent Ovarian Cancer: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial (NORA)
The US Food and Drug Administration approved niraparib for platinum-sensitive, recurrent ovarian cancer on the basis of results from the NOVA trial.1 Patients in the NOVA trial initially received niraparib at 300 mg, with dose reductions allowed for toxicity, per results from a phase 1 dose-escalation study.2 A subsequent retrospective analysis, however, suggested that an individualized starting dose of niraparib, based on the patient’s weight and platelet count, could improve the safety profile while maintaining efficacy.3 A phase 1 study of niraparib in Chinese patients with recurrent ovarian cancer showed that pharmacokinetics were similar to those observed in White patients.4
The double-blind, phase 3 NORA CONSORT trial evaluated the safety and efficacy of niraparib, administered at 2 different starting doses, in Chinese patients with platinum-sensitive recurrent ovarian cancer.5 Patients were stratified according to germline BRCA mutation status, response to the most recent chemotherapy, and time to progression after the penultimate platinum-based regimen. Study participants were then randomly assigned in a 2:1 ratio to receive niraparib (n=177) or placebo (n=88). Patients with a baseline body weight below 77 kg or a platelet count of less than 150,000/µL received niraparib at 200 mg daily, whereas all others received niraparib at 300 mg daily. The primary endpoint was PFS as determined by blinded central review.
At the time of the data analysis, 43% of patients in the niraparib arm and 13% of those in the placebo arm were still receiving treatment. The patients’ median age was 54.0 years (range, 35.0-78.0 years). Their median weight was 61.0 kg (range, 39.0-93.0 kg), and their median body mass index was 24.3 (standard deviation, 3.6). High-grade serous ovarian carcinoma was reported in 98.1% of patients. The time to progression following the penultimate platinum therapy was at least 12 months in 68.3% of patients, and 51.7% of patients had achieved a CR after their most recent platinum-based regimen. Germline BRCA mutations were observed in 37.7% of patients.
The NORA study achieved its primary endpoint, demonstrating a median PFS of 18.3 months (95% CI, 10.9 months to not estimable) with niraparib vs 5.4 months (95% CI, 3.7-5.7 months) with placebo (HR, 0.32; P<.0001; Figure 4). Nearly all subgroups benefited from niraparib. The median PFS with niraparib was superior in patients with or without a germline BRCA mutation (P<.0001). The NORA trial also achieved its secondary endpoints of extending the chemotherapy-free interval and the time to first subsequent therapy. The median chemotherapy-free interval was 18.5 months with niraparib vs 9.7 months with placebo (HR, 0.34; 95% CI, 0.24-0.48; P<.0001; Figure 5). The time to first subsequent therapy was 16.7 months with niraparib vs 7.7 months with placebo (HR, 0.35; 95% CI, 0.25-0.50; P<.0001). OS data were immature and did not show a difference between the 2 arms (P=.267).
Grade 3 or higher treatment-emergent adverse events were reported in 50.8% of patients in the niraparib arm vs 19.3% in the placebo arm. Treatment-related adverse events of grade 3 or higher were observed in 44.6% vs 11.4%, respectively. Serious treatment-related, treatment-emergent adverse events were more common in the niraparib arm (13.0% vs 4.5%), as were treatment-related adverse events leading to dose reduction (59.9% vs 13.6%). Discontinuation rates were similar in the 2 arms (4.0% vs 5.7%, respectively). The most common adverse events of any grade in the niraparib arm included white blood cell count decrease (59.3%), neutrophil count decrease (58.8%), and platelet count decrease (54.8%).
References
1. Mirza MR, Monk BJ, Herrstedt J, et al; ENGOT-OV16/NOVA Investigators. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375(22):2154-2164.
2. Sandhu SK, Schelman WR, Wilding G, et al. The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial. Lancet Oncol. 2013;14(9):882-892.
3. Berek JS, Matulonis UA, Peen U, et al. Safety and dose modification for patients receiving niraparib. Ann Oncol. 2018;29(8):1784-1792.
4. Zhang J, Zheng H, Gao Y, et al. Phase I pharmacokinetic study of niraparib in Chinese patients with epithelial ovarian cancer. Oncologist. 2020;25(1):19-e10.
5. Wu X, Yin R, Yang J, et al. Individualized starting dose of niraparib in Chinese patients with platinum-sensitive recurrent ovarian cancer: a randomized, double-blind, placebo-controlled, phase 3 trial (NORA) [ESMO abstract LBA29]. Ann Oncol. 2020;31(suppl 4):S1160-S1161.
Primary Results From IMagyn050/GOG 3015/ENGOT-OV39, a Double-Blind Placebo-Controlled Randomized Phase 3 Trial of Bevacizumab-Containing Therapy +/– Atezolizumab for Newly Diagnosed Stage III/IV Ovarian Cancer
The double-blind, randomized phase 3 IMagyn050 trial evaluated atezolizumab vs placebo, in combination with bevacizumab, carboplatin, and paclitaxel, as first-line therapy in patients with epithelial ovarian, primary peritoneal, or fallopian tube cancer.1 Enrolled patients had stage III or IV cancer with macroscopic residual disease postoperatively or were candidates for neoadjuvant therapy with planned interval surgery. The patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. All patients received either atezolizumab (1200 mg) or placebo in combination with paclitaxel (175 mg/m2), carboplatin (area under the curve [AUC], 6 mg/mL·min), and bevacizumab (15 mg/kg) every 3 weeks. After the first 6 cycles, patients continued treatment with bevacizumab and either atezolizumab or placebo for cycles 7 to 22. The primary endpoints were PFS based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and OS.
The intention-to-treat population included 650 patients in the atezolizumab arm and 651 in the placebo arm. PD-L1 was detected in at least 1% of immune cells in 60% of patient. The median PFS in the intention-to-treat population was 18.4 months with placebo vs 19.5 months with atezolizumab (HR, 0.92; 95% CI, 0.79-1.07; P=.2785; Figure 6).
Among patients with at least 1% PD-L1 expression in the immune cell infiltrate, the median PFS was 18.5 months with placebo vs 20.8 months with atezolizumab (HR, 0.80; 95% CI, 0.65-0.99; P=.0376). OS data at the first interim analysis were immature. The median OS in the intention-to-treat population was not evaluable for either arm (HR, 0.96; 95% CI, 0.74-1.26; P=.7887). Among patients with at least 1% PD-L1 expression in the immune cells, the median OS was 31.2 months with placebo vs not evaluable with atezolizumab (HR, 0.98; 95% CI, 0.68-1.41; P=.9083). Subgroup analysis suggested a potential benefit with atezolizumab in patients who had stage III disease (HR, 0.80; 95% CI, 0.67-0.97). However, subgroups based on age, race, baseline ECOG performance status, treatment approach, and histology did not show a benefit with atezolizumab vs placebo. Treatment with atezolizumab appeared beneficial among patients with at least 5% PD-L1 expression in immune cells in the tumor section (HR, 0.64; 95% CI, 0.43-0.96) and among patients with at least 1% PD-L1 expression in the tumor cells (HR, 0.41; 95% CI, 0.19-0.90).
The safety profile of the novel treatment combination was consistent with prior observations. Serious adverse events were observed in 33% of patients in the placebo arm vs 47% in the atezolizumab arm. Treatment-related serious adverse events were observed in 21% vs 35%, respectively.
Reference
1. Moore K, Bookman MA, Sehouli J, et al. Primary results from IMagyn050/GOG 3015/ENGOT-OV39, a double-blind placebo-controlled randomized phase 3 trial of bevacizumab-containing therapy +/– atezolizumab for newly diagnosed stage III/IV ovarian cancer [ESMO abstract LBA31]. Ann Oncol. 2020;31(suppl 4):S1162-S1163.
Efficacy and Safety of Niraparib in Older Patients With Advanced Ovarian Cancer: Results From the PRIMA/ENGOT-OV26/GOG-3012 Trial
The standard-of-care treatment for ovarian cancer is the same for older and younger patients, but older patients may be at greater risk for severe toxicities and treatment discontinuation.1 The PRIMA trial evaluated the safety and efficacy of niraparib maintenance therapy among patients with ovarian cancer who responded to first-line treatment with a platinum-based regimen. An earlier analysis reported a median PFS of 13.8 months with niraparib vs 8.2 months with placebo (HR, 0.62; 95% CI, 0.50-0.76; P<.001) among patients in the intention-to-treat population.2 A retrospective study examined the effect of age on the safety and efficacy of niraparib in the PRIMA trial.3 For the evaluation of outcomes, patients were divided into age groups of younger than 65 years vs 65 years or older, and of younger than 75 years vs 75 years or older. Progression was assessed by computed tomography or magnetic resonance imaging every 12 weeks. Patient-related outcomes were assessed by means of questionnaires administered at screening, throughout treatment, and at 4, 8, 12, and 24 weeks after the last dose of niraparib or placebo.
Among 733 enrolled patients, 444 were younger than 65 years and 289 were 65 years or older; 657 patients were younger than 75 years and 76 were 75 years or older. Patients ages 65 years or older and 75 years or older were more likely than younger patients to have a high ECOG performance status score at baseline. Patients age 75 years or older were more likely to have stage IV disease. Homologous recombination proficiency was more common in patients ages 65 years or older and 75 years or older. Neoadjuvant chemotherapy was administered at similar rates to all age groups.
Among patients younger than 65 years, the median PFS was 13.9 months with niraparib vs 8.3 months with placebo (HR, 0.61; 95% CI, 0.47-0.81). Among those 65 years or older, the median PFS was 13.7 months vs 8.1 months, respectively (HR, 0.53; 95% CI, 0.39-0.74). Niraparib was also superior to placebo in patients who were younger than 75 years (median PFS, 13.8 vs 8.2 months; HR, 0.62; 95% CI, 0.50-0.77) and in those 75 years or older (median PFS, 13.8 vs 5.6 months; HR, 0.37; 95% CI, 0.17-0.81).
Across all age cohorts, treatment-emergent adverse events were more frequent with niraparib compared with placebo. Rates of treatment-emergent adverse events were generally similar in patients younger than 65 years vs those 65 years or older, as well as in patients younger than 75 years vs those 75 years or older. Among patients treated with niraparib, thrombocytopenia of any grade was reported in 70.5% of those 65 years or older vs 63.6% in younger patients. Grade 3 or higher thrombocytopenia was reported in 45.8% vs 34.4%, respectively. Similarly, thrombocytopenia of any grade was more common among patients 75 years or older than in younger patients (77.8% vs 64.9%), as was thrombocytopenia of grade 3 or higher (53.7% vs 37.0%). Tailoring the dose of niraparib based on patient characteristics reduced the rates of grade 3 or higher thrombocytopenia from 42.8% to 18.0% in patients younger than 65 years and from 57.0% to 26.1% in older patients (Figure 7). Similarly, a personalized dosing regimen was associated with a reduction in the rate of grade 3 or higher thrombocytopenia in patients younger than 75 years (from 46.4% to 19.7%) and in those 75 years or older (from 62.2% to 35.3%). Patient-related outcomes, including FOSI scores and EQ-5D-5L results, were similar across all age cohorts.
References
1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer. Version 1.2020. https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf. Updated March 11, 2020. Accessed October 20, 2020.
2. González-Martín A, Pothuri B, Vergote I, et al; PRIMA/ENGOT-OV26/GOG-3012 Investigators. Nira-parib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2019;381(25):2391-2402.
3. Valabrega G, Pothuri B, Oaknin A, et al. Efficacy and safety of niraparib in older patients with advanced ovarian cancer: results from the PRIMA/ENGOT-OV26/GOG-3012 trial [ESMO abstract 819P]. Ann Oncol. 2020;31(suppl 4):S619.
Maintenance Olaparib Plus Bevacizumab in Patients With Newly Diagnosed, Advanced High-Grade Ovarian Carcinoma
Olaparib was investigated as a maintenance therapy in combination with bevacizumab in the phase 3 PAOLA-1/ENGOT-ov25 trial.1,2 The trial enrolled women with stage III/IV, high-grade serous or endometrioid ovarian, fallopian tube, and/or primary peritoneal cancer. Enrolled patients had responded to first-line therapy with platinum and a taxane, plus at least 2 cycles of bevacizumab. All patients received bevacizumab (15 mg/kg every 3 weeks) for a total of 15 months. In addition, patients were randomly assigned in a 2:1 ratio to receive olaparib tablets (300 mg) or placebo twice daily for 2 years. Stratification factors included presence of the BRCA mutation and first-line response. The primary endpoint was investigator-assessed PFS according to RECIST 1.1. In the primary analysis of PAOLA-1, the median PFS was 22.1 months with olaparib plus bevacizumab vs 16.6 months with bevacizumab alone (HR, 0.59; 95% CI, 0.49-0.72; P<.001).2
The PAOLA-1 trial included a secondary endpoint of PFS2, which was measured from the time of randomization to second progression or death.1 The prespecified analysis of PFS2 was planned for approximately 53% data maturity or 1 year after the primary analysis. The median follow-up was 35.5 months in the olaparib arm and 36.5 months in the placebo arm. A significant PFS2 benefit was observed with the addition of olaparib to bevacizumab in the intention-to-treat population, with a median PFS2 of 36.5 months in the olaparib arm vs 32.6 months in the placebo arm (HR, 0.78; 95% CI, 0.640.95; P=.0125). PARP inhibitors were administered during the first subsequent treatment to 9.1% of patients in the olaparib arm vs 26.8% in the placebo arm. A subgroup analysis showed a superior median PFS2 with olaparib vs placebo among patients with HRD-positive disease. This improvement was observed in an analysis that included patients with the BRCA mutation (50.3 vs 35.3 months; HR, 0.56; 95% CI, 0.41-0.77), as well as in an analysis that excluded these patients (50.3 vs 30.1 months; HR, 0.60; 95% CI, 0.38-0.96). The median PFS2 was similar in patients with negative or unknown HRD status (26.3 vs 28.1 months; HR, 0.98; 95% CI, 0.77-1.27). The PFS2 improvement was supported by a significant increase in time to second subsequent therapy in the intention-to-treat population (38.2 vs 31.5 months; HR, 0.78; 95% CI, 0.64-0.95; P=.0115). OS data were immature, and did not reveal a survival difference between the olaparib arm and the placebo arm. The median OS was not reached with olaparib vs 45.8 months with placebo (HR, 0.93; 95% CI, 0.74-1.18; P=.5631). No new safety signals were observed.
A separate analysis evaluated response rates among the 216 patients with evidence of disease according to RECIST and/or CA-125 levels at least twice the upper level of normal at study entry.3 Baseline characteristics were generally well balanced between the cohorts. Approximately 75% of patients had undergone surgery. The BRCA mutation was observed in 21% of patients in the olaparib arm vs 26% of those in the placebo arm; 37% vs 45% of patients, respectively, were HRD-positive. Treatment was discontinued by 78% of patients in the olaparib arm vs 82% in the placebo arm. Reasons included progression (58% vs 71%) and adverse events or symptomatic progression (16% vs 4%).
Among patients with the BRCA mutation, the objective response rate (ORR) was 64% (18/28) with olaparib plus bevacizumab vs 42% (8/19) with placebo plus bevacizumab (Figure 8). Among the HRD-positive patients, including those with the BRCA mutation, the ORR was 53% (26/49) with olaparib vs 31% (10/32) with placebo. Among HRD-positive patients with BRCA-negative tumors, the ORR was 32% (6/19) with olaparib vs 21% (3/14) with placebo. In patients who were HRD-negative, the ORR was 13% (7/56) with olaparib vs 15% (4/27) with placebo.
Patients with evidence of disease or elevated CA-125 levels at study entry comprised 30% of the olaparib arm vs 25% of the control arm. Among patients with elevated CA-125 levels at study entry, ORR was 36% with olaparib plus bevacizumab vs 29% with placebo plus bevacizumab. Similarly, among the entire cohort of patients with evidence of disease and/or elevated CA-125 at baseline, ORR was 35% vs 28%, respectively.
References
1. González-Martín A, Tazi Y, Heitz F, et al. Maintenance olaparib plus bevacizumab in patients with newly diagnosed advanced high-grade ovarian carcinoma: final analysis of second progression-free survival in the phase III PAOLA-1/ENGOTov25 trial [ESMO abstract LBA33]. Ann Oncol. 2020;31(suppl 4):S1163-S1164.
2. Ray-Coquard I, Pautier P, Pignata S, et al; PAOLA-1 Investigators. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N Engl J Med. 2019;381(25):2416-2428.
3. Colombo N, Gantzer J, Ataseven B, et al. Maintenance olaparib + bevacizumab in patients with newly diagnosed advanced high‐grade ovarian cancer: RECIST and/or CA‐125 objective response rate in the phase III PAOLA‐1 trial [ESMO abstract 812MO]. Ann Oncol. 2020;31(suppl 4):S614.
Health-Related Quality of Life in Patients With Newly Diagnosed Stage III or IV Ovarian Cancer Treated With Veliparib + Chemotherapy Followed by Veliparib Maintenance
Health-related quality of life was evaluated in the phase 3 VELIA trial of veliparib in patients with newly diagnosed, advanced-stage ovarian cancer.1,2 After stratification according to surgery, residual disease, paclitaxel schedule, disease stage, geographic region, and germline BRCA mutation status, 1140 patients were randomly assigned to 1 of 3 arms. Patients in the control arm received placebo and carboplatin (every 3 weeks)/paclitaxel (every 1 or 3 weeks) for 6 cycles, followed by placebo monotherapy. Patients in the veliparib arm received veliparib (150 mg twice daily) and carboplatin/paclitaxel for 6 cycles, followed by placebo monotherapy. Patients in the veliparib maintenance arm were treated with 6 cycles of veliparib, carboplatin, and paclitaxel followed by maintenance veliparib monotherapy (400 mg twice daily) for cycles 7 to 36.
The VELIA trial met its primary endpoint. The median PFS was 34.7 months with veliparib maintenance vs 22.0 months with placebo (HR, 0.44; 95% CI, 0.28-0.68; P<.001). Veliparib maintenance improved the median PFS in the intention-to-treat population and in the subgroup of HRD-positive patients (P<.001).
The trial investigators assessed health-related quality of life through administration of the National Comprehensive Cancer Network Functional Assessment of Cancer Therapy Ovarian Symptom Index–18 (NFOSI-18) and the EQ-5D-5L.2 The rate of on-study adherence was greater than 90%. Baseline demographics were similar among all 3 treatment arms. The NFOSI-18 questionnaire generates information in 4 domains. Scores improved in the domains of disease-related symptoms (Figure 9), side effects, and functional well-being across all 3 arms. Improvements in the veliparib maintenance arm were smaller than those observed in the other 2 arms; however, no meaningful clinical differences were observed between the veliparib maintenance arm and the placebo arm. Emotional well-being scores remained between 0 and 1 for all 3 arms throughout the 35 weeks queried.
Similar outcomes were observed with the EQ-5D-5L questionnaire. Both the health index score and the overall health score improved across all 3 treatment arms. Scores from the veliparib maintenance arm were numerically lower than those in the placebo arm, but the difference was not clinically meaningful. Time to symptom worsening was similar for all 3 treatments, according to the NFOSI-18 questionnaire. Across the 3 treatment arms, time to symptom worsening ranged from 9.8 to 10.2 months for emotional well-being, from 6.5 to 7.7 months for treatment side effects, and from 6.9 to 8.1 months for functional well-being.
References
1. Coleman RL, Fleming GF, Brady MF, et al. Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer. N Engl J Med. 2019;381(25):2403-2415.
2. Cella D, Bookman M, Steffensen KD, et al. Health-related quality of life in patients with newly diagnosed stage III or IV ovarian cancer treated with veliparib + chemotherapy followed by veliparib maintenance [ESMO abstract 809MO]. Ann Oncol. 2020;31(suppl 4):S612.
Highlights in Ovarian Cancer From the European Society for Medical Oncology Virtual Congress 2020: Commentary
Thomas J. Herzog, MD
Several presentations at the European Society for Medical Oncology (ESMO) Virtual Congress 2020 provided important insights into the management of patients with ovarian cancer. Data were presented on the poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors olaparib and niraparib, as well as novel immunotherapy and chemotherapy regimens.
PARP Inhibitors
Olaparib
Dr Susana Banerjee and colleagues provided an updated analysis of the SOLO-1 trial.1 This trial compared olaparib vs placebo among patients with newly diagnosed ovarian cancer. The patients had stage III/IV disease (per criteria from the International Federation of Gynecology and Obstetrics) with high-grade serous or endometrioid histology and confirmed BRCA mutations. They had an Eastern Cooperative Oncology performance status of 0 or 1. Patients had undergone cytoreductive surgery, and they had a complete response or a partial response after receiving platinum-based chemotherapy. The patients were randomly assigned 2:1 to maintenance therapy with olaparib (n=260) or placebo (n=131). Patients were treated for up to 2 years (and some were treated beyond 2 years). The primary endpoint was investigator-assessed progression-free survival (PFS). An initial report was published in 2018.2 The median PFS was not reached with olaparib vs 13.8 months with the control. In the updated analysis presented at the 2020 ESMO meeting, the final median PFS was 56.0 months with olaparib vs 13.8 months with the control (hazard ratio [HR], 0.33; 95% CI, 0.25-0.43).1 The median duration of treatment in the olaparib arm was 25 months, which suggests a sustained clinical effect even after treatment cessation. Among the subgroup of patients who had developed a complete response to platinum therapy, the median PFS was not reached in the olaparib arm vs 15.3 months in the placebo arm (HR, 0.37).
The delta in the median PFS between the treatment groups exceeded 42 months. It is rare to see such a large difference between 2 experimental arms in a clinical trial. These results are remarkable because they allow clinicians to consider the significant magnitude of effect observed with use of frontline maintenance PARP inhibitors in patients with a BRCA mutation. These data are practice-changing, in that PARP inhibitors continue to be used in new roles that are reinforced with impressive data from each subsequent trial. Several active PARP inhibitors are now approved for the treatment of ovarian cancer. These data contribute to the overall findings that PARP inhibitors are extremely effective in this setting, especially for patients with a BRCA mutation, as well as those with homologous recombination deficiency ([HRD]; notably, only BRCA-mutated patients were included in the SOLO-1 trial).
Another important finding is that no new safety signals were observed, and the trial did not demonstrate a spike in myelodysplastic syndromes (MDS) or acute myelogenous leukemia (AML). This observation is important because the SOLO-2 trial of platinum-sensitive maintenance therapy showed an increase in MDS/AML.3 The rate of MDS reached 8% in the long-term analysis of overall survival, which exceeded 12 months and favored the olaparib arm. Fortunately, SOLO-1 did not show a similar increase despite the longer follow-up, which is reassuring in this primary setting.1 Further surveillance is needed to confirm the safety of long-term treatment, as well as to evaluate the possibility of reaching the elusive goal of curing more women in the frontline setting by adding PARP inhibition maintenance. The possibility of this exciting outcome was raised by the SOLO-1 clinical trial, and thus we eagerly await mature overall survival data.
Niraparib
Dr Bhavana Pothuri and colleagues presented patient-reported outcomes from the PRIMA trial, which evaluated the use of niraparib in patients with newly diagnosed stage III/IV ovarian cancer at high risk for recurrence.4,5 The trial enrolled patients with a complete response or a partial response after 6 to 9 cycles of first-line platinum-based chemotherapy. The patients were randomly assigned in a 2:1 ratio to maintenance with niraparib or placebo. The primary endpoint was PFS among HRD-positive patients and in the overall intention-to-treat population, as determined by hierarchical testing. Niraparib improved PFS in both subgroups. Among HRD-positive patients, the median PFS was 21.9 months with niraparib vs 10.4 months with placebo (HR for disease progression or death, 0.43; 95% CI, 0.31-0.59; P<.001). In the overall population, the PFS was 13.8 months vs 8.2 months, respectively (HR, 0.62; 95% CI, 0.50-0.76; P<.001).
This trial administered treatment for 36 months, which raised the question of whether patients would experience any significant detrimental effects that would not be captured by standard toxicity reporting. To assess patient-reported outcomes, the PRIMA investigators administered questionnaires at baseline, every 8 weeks for the first 56 weeks, and then every 12 weeks. The questionnaires included the Functional Assessment of Cancer Therapy–Ovarian Symptom Index,6 the European Quality of Life 5-Dimension 5-Level questionnaire,7 the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire,8 and the EORTC Quality of Life Questionnaire Ovarian Cancer module.9
No statistically significant differences between niraparib and placebo were identified by any of the patient-reported outcome instruments. It appeared that patients in the niraparib arm experienced no detrimental effects, despite receiving active therapy for many years. Another reassuring observation is that the reporting adherence rates were very high, which is unusual in these types of studies. There is typically a tremendous drop-off, especially in the placebo arm and in patients with progressive disease. This finding speaks to a very well-conducted study, in that more than 80% of the patients completed the questionnaires.
Quality of life was comparable between the treatment arms, as were reports of gastrointestinal symptoms. These results are similar to the patient-reported outcomes from the NOVA trial, which evaluated niraparib in platinum-sensitive recurrent ovarian cancer.10 Niraparib did not have a detrimental impact in the NOVA trial. Most of the toxicities associated with niraparib are laboratory-based, and do not greatly impact the patient’s quality of life. For example, a low platelet count—as long as there is no bleeding—will not measurably impact a patient’s quality of life. This analysis provides reassuring data for patients who receive PARP inhibitors as maintenance therapy for many years.
A concern related to assessment of patient-reported outcomes is the quality of the tools. The conclusions are only as strong as the available tools. Analysis of the PRIMA trial appeared to provide an accurate assessment.4 In other studies, however, there have been discrepancies between treatment toxicity profiles and patient-reported outcomes. It appears that some instruments can miss the impact that toxicities have on quality of life. Investigators should continue to explore patient-related outcomes in clinical trials, and more sensitive tools are needed.
Dr Giorgio Valabrega and colleagues reported on the efficacy and safety of niraparib in older patients with advanced ovarian cancer.11 This analysis is based on data from the PRIMA trial.5 It should be noted that after a study amendment, approximately one-third of patients in the PRIMA trial received an individualized starting dose based on their body weight and platelet count. Among the 733 patients enrolled in the trial, 444 were younger than 65 years, and 289 were ages 65 years or older. The trial enrolled 76 patients ages 75 years or older, leaving 657 patients younger than 75 years. The efficacy of niraparib was comparable among all age groups. If anything, the benefit of niraparib might have been stronger in older patients. Among patients younger than 65 years, the median PFS was 13.9 months with niraparib vs 8.2 months with placebo (HR, 0.61; 95% CI, 0.47-0.81). Among patients ages 65 years and older, the median PFS was 13.7 months vs 8.1 months, respectively (HR, 0.53; 95% CI, 0.39-0.74). The treatment-emergent adverse events were similar among the age groups. Quality of life did not appear to differ.
Overall, this analysis showed that the efficacy of niraparib was not decreased in older patients. It is clear that niraparib can be used to successfully treat geriatric patients. An encouraging finding is that, with the individualized starting dose of niraparib, rates of thrombocytopenia, anemia, and neutropenia were significantly reduced. Most toxicities were similar between younger and older patients. Thrombocytopenia occurred in 64% of patients younger than 65 and in 78% of those 75 years and older, while grade 3/4 thrombocytopenia occurred in 34% of patients younger than 65 and in 54% of those ages 75 years and older. This analysis supported the use of PARP inhibitors in older patients. Efficacy was not diminished, and toxicity—with the exception of thrombocytopenia—was similar between younger and older patients.
Dr Xiaohua Wu and coworkers presented the phase 3 NORA trial, which evaluated an individualized starting dose of niraparib among 240 Chinese patients with platinum-sensitive recurrent ovarian cancer and either a germline BRCA mutation or a high-grade serous histologic subtype.12 The patients had a complete or partial response to the platinum therapy. This trial was conducted in 32 centers in China; the data were not drawn from a larger trial, as is often the case for data sets focusing on certain demographic features. Previous phase 1 data appeared to show similar pharmacokinetics between White and Chinese patients treated with niraparib.13 The NORA trial aimed to identify any differences in metabolism, pharmacokinetics, or other issues that could impact efficacy or toxicity.
The individualized starting dose of niraparib was introduced into the PRIMA trial after the enrollment of approximately two-thirds of patients, and this modification prospectively demonstrated the reduction in hematologic toxicity—especially thrombocytopenia—with niraparib.5 The NORA trial was initiated after the PRIMA trial, and the investigators administered an individualized starting dose to all but 16 patients.
The 256 patients were randomly assigned to niraparib or placebo in a 2:1 ratio. The individualized starting dose of niraparib was based on “weights and plates.” The dose was 200 mg/day for patients whose body weight at baseline was less than 77 kg or whose platelet count was less than 150,000/µL. The dose was 300 mg in all other patients (including the 16 patients treated before the dosing amendment). The primary endpoint was PFS according to blinded independent review. The median PFS was 18.3 months with niraparib vs 5.4 months with placebo (HR, 0.32; 95% CI, 0.23-0.45; P<.0001). Rates of grade 3 or higher treatment-emergent adverse events were higher in the niraparib arm, and mostly consisted of neutropenia and platelet-count disturbances or anemia. Data from breast cancer and other malignancies have suggested that some patients exhibit idiosyncratic pharmacokinetics after treatment with PARP inhibitors,14 but this has not been seen in patients with ovarian cancer. Data from the NORA trial were reassuring, in that the benefits previously seen with niraparib were maintained among Chinese patients.
In terms of toxicity, it appears that the individualized starting dose was equal to the standard dose. There were no new safety signals in the study. The individualized dose appeared to decrease the amount of platelet abnormalities. In the niraparib arm, only 11% of patients developed grade 3 or higher thrombocytopenia. Overall, the results of the NORA study were very encouraging, supporting the applicability of niraparib in the real world while providing insight into the most effective use of PARP inhibitors in these patients.
Immunotherapy
Atezolizumab
Dr Kathleen Moore and colleagues presented results of the randomized phase 3 IMagyn050/GOG 3015/ENGOT-OV39 trial, which compared atezolizumab plus bevacizumab vs bevacizumab alone in patients with newly diagnosed stage III/IV ovarian cancer.15 Atezolizumab is a programmed death ligand 1 (PD-L1) checkpoint inhibitor that has demonstrated efficacy in other cancers.16,17 Some data have shown that immuno-oncology agents have some effects in ovarian cancer,18 even though this disease does not have a high mutational burden. Furthermore, there is reason to believe that the combination of an immuno-oncology agent and a vascular endothelial growth factor blocker might promote T-cell infiltration in the tumor bed. This activity boosts the anti-tumor immune response and decreases the amount of T suppressor cells associated with a hypoxic microenvironment, which is reversed with improved blood flow. There is also some thought that normalizing or “pruning” the vessels will increase drug delivery. This effect might help these agents work together following chemotherapy.
This trial enrolled 1301 patients with newly diagnosed untreated stage III/IV ovarian cancer who underwent either primary cytoreductive surgery with gross residual disease (if stage III) or neoadjuvant chemotherapy and interval surgery.15 The patients had a performance status of 0 to 2. All patients received treatment with carboplatin and paclitaxel (cycles 1-6) plus bevacizumab (cycles 1-22, except for perioperative cycles). Patients were randomly assigned to receive this treatment with atezolizumab or placebo, for up to 22 cycles. The co–primary endpoints were investigator-assessed PFS and overall survival. The PFS was statistically assessed in the PD-L1 and intention-to-treat populations, simultaneously using a P value threshold of <.002. Stratification factors included stage, performance status, adjuvant vs neoadjuvant treatment, and PD-L1 status (immunohistochemistry <1% vs >1%; per the Ventana SP142 assay). The demographic factors were well balanced between the treatment groups.
Unfortunately, there was no significant difference in PFS between the treatment arms. In the intention-to-treat population, the median PFS was 19.5 months with atezolizumab vs 18.4 months without atezolizumab (HR, 0.92; 95% CI, 0.79-1.07; P=.2785). Among the PD-L1–positive patients, the median PFS was 20.8 months vs 18.5 months, respectively (HR, 0.80; 95% CI, 0.65-0.99; P=.0376, where the threshold for significance was set at P<.002). Still, the Kaplan-Meier curves were very close. Data for overall survival were too immature for meaningful assessment. There were no major differences in safety outcomes, and no new safety signals were identified.
There might have been a signal that atezolizumab was beneficial in patients with PD-LI immunohistochemistry staining on tumor-infiltrating immune cells of 5% or higher. It might be necessary to use a cutoff exceeding 10% to identify patients who might benefit. Many of the cutoffs were derived from other cancers, such as lung cancer, and therefore might not be applicable in ovarian cancer; furthermore, the tumor mutational burden for ovarian cancer is relatively low. It remains to be seen whether there could be an advantage in these populations with a higher PD-L1 cut point. Among the group of patients with the highest level of PD-L1 expression (≥5), the unstratified HR was 0.64.
It is unfortunate that this trial did not meet the primary endpoint. There was not even a clinically meaningful trend for PFS improvement in the overall population. It would be of interest to perform an exploratory analysis in the population of patients with PD-L1 expression of 5% or higher. Data for overall survival will also be of interest. In the past, some trials of immunotherapy in ovarian cancer showed modest to very minimal gains in PFS, but then showed a significant improvement in overall survival
Immunotherapy with the checkpoint inhibitor avelumab did not improve outcome in previous studies, such as the frontline JAVELIN 100 trial.19 The JAVELIN 200 trial of platinum-resistant ovarian cancer was also a negative trial.20 These trials did not evaluate outcome according to PD-L1 status. The IMagyn050/GOG 3015/ENGOT-OV39 trial highlighted the importance of incorporating PD-L1 expression. There is no question that immuno-oncology agents are extremely active. However, it appears that ovarian cancers are too “cold” to benefit. Basic science research is needed to explore the possibility of altering these cold tumors into hot tumors to increase the efficacy of immuno-oncology agents. More translational science is needed before hundreds of millions of more dollars are invested into randomized phase 3 trials.
Durvalumab
Dr Yvette Drew presented results of the phase 2 MEDIOLA trial, which evaluated olaparib plus durvalumab and bevacizumab in patients with nongermline, BRCA-mutated platinum-sensitive relapsed ovarian cancer.21 It is thought that PARP inhibition creates more neoantigens that upregulate PD-L1 expression, thereby increasing DNA damage and thus making these agents more effective. Previous data have shown that the combination of vascular endothelial growth factor inhibitors and PARP inhibitors increased PFS in patients with ovarian cancer.22 The initial cohort analysis of MEDIOLA showed that olaparib plus durvalumab was well tolerated and had good clinical activity. Additional cohorts were added to test the combination of a PARP inhibitor plus an immuno-oncology agent, with or without bevacizumab.
The trial enrolled patients who had received 2 or fewer prior lines of therapy.21 The patients had not received a PARP inhibitor or an immuno-oncology agent. The patients’ median age was similar between the treatment groups. The primary endpoint was the rate of disease control at 24 weeks, with the efficacy target set at 80%. The target was 80%. Secondary endpoints encompassed safety and tolerability. This small study treated just over 30 patients in each arm.
The disease control rate at 24 weeks was 77% with the triplet combination vs 28% with the doublet. The median PFS was 14.7 months vs 5.5 months, respectively. The duration of response was 11.1 months in the triplet arm vs 6.9 months in the doublet arm.
The conclusion of this trial was that the triplet showed promising efficacy in patients without a BRCA germline mutation. The high overall response rate seen with the triplet regimen was not driven by genomic instability status, as the overall response rate exceeded 75% in patients with or without genomic instability. There were no new safety signals. The ongoing phase 3 DUO-O trial is evaluating the combination of olaparib, durvalumab, and bevacizumab.23
These data are interesting. In my opinion, however, the trial is missing a treatment arm. It would have been informative to understand the contribution effect of each agent by including a durvalumab and bevacizumab cohort. I am skeptical that the use of another checkpoint inhibitor can significantly improve outcomes in an unselected population in the frontline ovarian cancer setting. Data from the upcoming DUO-O study should provide insight into this important question.
Chemotherapy
Paclitaxel
Dr Andrew Clamp presented the final analysis of the ICON8 trial.24 It was promising to learn about the concept of dose-dense chemotherapy in the frontline setting for ovarian cancer, as studied in the JGOG 3016 trial.25,26 This trial showed significant gains in PFS and overall survival by changing the administration of paclitaxel from every 3 weeks to every week. The results led to several other trials that evaluated whether an alteration in the dosing schedule—whereby a higher amount of the drug is given over a similar or shorter period—would improve efficacy outcomes. The GOG-262 trial evaluated paclitaxel plus carboplatin given every week or every 3 weeks, with or without bevacizumab.27 A drawback to the trial design is that patients could choose whether they received bevacizumab. More than 80% of the patients opted to receive this treatment. The primary analysis for the overall patient group showed no differences in outcomes between paclitaxel administered at a dose-dense regimen vs the traditional regimen of once every 3 weeks. A post-hoc analysis of the subgroup of patients who did not receive bevacizumab showed that the dose-dense regimen was superior in this cohort. The post-hoc nature of this analysis, however, means that the results are hypothesis-generating only. The conclusion from the GOG-262 study is that there was no difference between the dose-dense and standard-treatment arms. Overall, the dose-dense paclitaxel regimen was well tolerated, but it was associated with more anemia and sensory neuropathy.
A similar trial, MITO-7, compared carboplatin plus paclitaxel given every 3 weeks in the traditional regimen vs carboplatin at an AUC of 2 and paclitaxel at 60 mg/m2 given on days 1, 8, and 15.28 Again, there was no difference in outcome. The HR for PFS was 0.88, which was not statistically significant. The dose-dense arm was associated with slightly increased neuropathy.
The ICON8 trial evaluated 3 regimens: carboplatin at an area under the curve (AUC) of 5 and paclitaxel at 175 mg/m2 every 3 weeks; fractionated paclitaxel at 80 mg/m2 every week, with carboplatin every 3 weeks; and fractionated doses of both agents, with carboplatin at an AUC of 2 every week and paclitaxel at 80 mg/m2 every week.24 The trial enrolled more than 1500 patients, including those with stage IC through IV disease. Patients had undergone either primary cytoreduction or interval cytoreduction with neoadjuvant chemotherapy. The trial had 2 co–primary endpoints, PFS and overall survival, and the target for the HR was 0.75. Earlier analyses were published in 2019 and 2020.29,30
There was no difference in PFS between the treatment arms. Because the Kaplan-Meier curves were not proportional, a restricted-means analysis was used. Both weekly treatment arms were associated with increased grade 3/4 toxicity, which was mostly neutropenia. Importantly, there was no increase in neurotoxicity, as was seen in other trials of dose-dense therapy. The regimen of carboplatin plus paclitaxel given every 3 weeks should remain the standard of care for frontline treatment in the majority of patients with ovarian cancer. The dose-dense regimen is associated with some increased toxicity, plus extra cost, without any significant improvement in outcome.
Disclosure
Dr Herzog has served on the scientific advisory boards of AstraZeneca, Caris, Clovis, Genentech, GSK, Johnson & Johnson, and Merck.
References
1. Banerjee S, Moore K, Colombo N, et al. Maintenance olaparib for patients with newly diagnosed, advanced ovarian cancer and a BRCA mutation: 5-year follow-up from SOLO1 [ESMO abstract 811MO]. Ann Oncol. 2020;31(suppl 4):S613.
2. Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;379(26):2495-2505.
3. Pujade-Lauraine E, Ledermann JA, Selle F, et al; SOLO2/ENGOT-Ov21 investigators. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(9):1274-1284.
4. Pothuri B, Han S, Chase D, et al. Patient-reported outcomes in patients receiving niraparib in the PRIMA/ENGOT-OV26/GOG-3012 trial [ESMO abstract 810MO]. Ann Oncol. 2020;31(suppl 4):S612-S613.
5. González-Martín A, Pothuri B, Vergote I, et al; PRIMA/ENGOT-OV26/GOG-3012 Investigators. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2019;381(25):2391-2402.
6. Beaumont J, Yount S, Lalla D, et al. Validation of the Functional Assessment of Cancer Therapy-Ovarian (FACT-O) Symptom Index (FOSI) in a phase II clinical trial of pertuzumab in patients with advanced ovarian cancer [ASCO abstract 16021]. J Clin Oncol. 2007;25(18 suppl).
7. Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011;20(10):1727-1736.
8. Groenvold M, Klee MC, Sprangers MAG, Aaronson NK. Validation of the EORTC QLQ-C30 quality of life questionnaire through combined qualitative and quantitative assessment of patient-observer agreement. J Clin Epidemiol. 1997;50(4):441-450.
9. Greimel E, Bottomley A, Cull A, et al; EORTC Quality of Life Group and the Quality of Life Unit. An international field study of the reliability and validity of a disease-specific questionnaire module (the QLQ-OV28) in assessing the quality of life of patients with ovarian cancer. Eur J Cancer. 2003;39(10):1402-1408.
10. Mirza MR, Monk BJ, Herrstedt J, et al; ENGOT-OV16/NOVA Investigators. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375(22):2154-2164.
11. Valabrega G, Pothuri B, Oaknin A, et al. Efficacy and safety of niraparib in older patients with advanced ovarian cancer: results from the PRIMA/ENGOT-OV26/GOG-3012 trial [ESMO abstract 819P]. Ann Oncol. 2020;31(suppl 4):S619.
12. Wu X, Yin R, Yang J, et al. Individualized starting dose of niraparib in Chinese patients with platinum-sensitive recurrent ovarian cancer: a randomized, double-blind, placebo-controlled, phase 3 trial (NORA) [ESMO abstract LBA29]. Ann Oncol. 2020;31(suppl 4):S1160-S1161.
13. Zhang J, Zheng H, Gao Y, et al. Phase I pharmacokinetic study of niraparib in Chinese patients with epithelial ovarian cancer. Oncologist. 2020;25(1):e19-e10.
14. Sun K, Mikule K, Wang Z, et al. A comparative pharmacokinetic study of PARP inhibitors demonstrates favorable properties for niraparib efficacy in preclinical tumor models. Oncotarget. 2018;9(98):37080-37096.
15. Moore K, Bookman MA, Sehouli J, et al. Primary results from IMagyn50/GOG 3015/ENGOT-OV39, a double-blind placebo-controlled randomized phase 3 trial of bevacizumab-containing therapy +/– atezolizumab for newly diagnosed stage III/IV ovarian cancer [ESMO abstract LBA31]. Ann Oncol. 2020;31(suppl 4):S1162-S1163.
16. Herbst RS, Giaccone G, de Marinis F, et al. Atezolizumab for first-line treatment of PD-L1-selected patients with NSCLC. N Engl J Med. 2020;383(14):1328-1339.
17. Balar AV, Galsky MD, Rosenberg JE, et al; IMvigor210 Study Group. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 2017;389(10064):67-76.
18. Matulonis UA, Shapira R, Santin A, et al. Final results from the KEYNOTE-100 trial of pembrolizumab in patients with advanced recurrent ovarian cancer [ASCO abstract 6005]. J Clin Oncol. 2020;38(suppl).
19. Ledermann JA, Colombo N, Ozad AM, et al. Avelumab in combination with and/or following chemotherapy vs chemotherapy alone in patients with previously untreated epithelial ovarian cancer: results from the phase 3 JAVELIN Ovarian 100 trial [SGO abstract LBA 25]. https://www.sgo.org/wp-content/uploads/2020/03/SGO-2020-Annual-Meeting-Oral-Abstracts.pdf. Accessed October 27, 2020.
20. Pujade-Lauraine E, Fujiwara K, Ledermann JA, et al. Avelumab alone or in combination with pegylated liposomal doxorubicin versus pegylated liposomal doxorubicin alone in platinum-resistant or refractory epithelial ovarian cancer: primary and biomarker analysis of the phase III JAVELIN Ovarian 200 trial. Paper presented at: the Society of Gynecologic Oncology Annual Meeting; March 16-19, 2019; Honolulu, HI. Abstract LBA1.
21. Drew Y, Penson RT, O’Malley DM, et al. Phase II study of olaparib (O) plus durvalumab (D) and bevacizumab (B) (MEDIOLA): initial results in patients (pts) with non-germline BRCA-mutated (non-gBRCAm) platinum sensitive relapsed (PSR) ovarian cancer (OC) [ESMO abstract 814MO]. Ann Oncol. 2020;31(suppl 4):S615-S616.
22. Ray-Coquard I, Pautier P, Pignata S, et al; PAOLA-1 Investigators. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N Engl J Med. 2019;381(25):2416-2428.
23. ClinicalTrials.gov. Durvalumab treatment in combination with chemotherapy and bevacizumab, followed by maintenance durvalumab, bevacizumab and olaparib treatment in advanced ovarian cancer patients. (DUO-O). https://clinicaltrials.gov/ct2/show/NCT03737643. Identifier: NCT03737643. Accessed October 26, 2020.
24. Clamp AR, James EC, McNeish I, et al. ICON8: overall survival results in a GCIG phase III randomised controlled trial of weekly dose-dense chemotherapy in first line epithelial ovarian, fallopian tube or primary peritoneal carcinoma treatment [ESMO abstract 805O]. Ann Oncol. 2020;31(suppl 4):S610.
25. Katsumata N, Yasuda M, Takahashi F, et al; Japanese Gynecologic Oncology Group. Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial. Lancet. 2009;374(9698):1331-1338.
26. Katsumata N, Yasuda M, Isonishi S, et al; Japanese Gynecologic Oncology Group. Long-term results of dose-dense paclitaxel and carboplatin versus conventional paclitaxel and carboplatin for treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (JGOG 3016): a randomised, controlled, open-label trial. Lancet Oncol. 2013;14(10):1020-1026.
27. Chan JK, Brady MF, Penson RT, et al. Weekly vs. every-3-week paclitaxel and carboplatin for ovarian cancer. N Engl J Med. 2016;374(8):738-748.
28. Pignata S, Scambia G, Katsaros D, et al; Multicentre Italian Trials in Ovarian cancer (MITO-7); Groupe d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens et du sein (GINECO); Mario Negri Gynecologic Oncology (MaNGO); European Network of Gynaecological Oncological Trial Groups (ENGOT-OV-10); Gynecologic Cancer InterGroup (GCIG) Investigators. Carboplatin plus paclitaxel once a week versus every 3 weeks in patients with advanced ovarian cancer (MITO-7): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2014;15(4):396-405.
29. Clamp AR, James EC, McNeish IA, et al. Weekly dose-dense chemotherapy in first-line epithelial ovarian, fallopian tube, or primary peritoneal carcinoma treatment (ICON8): primary progression free survival analysis results from a GCIG phase 3 randomised controlled trial. Lancet. 2019;394(10214):2084-2095.
30. Blagden SP, Cook AD, Poole C, et al. Weekly platinum-based chemotherapy versus 3-weekly platinum-based chemotherapy for newly diagnosed ovarian cancer (ICON8): quality-of-life results of a phase 3, randomised, controlled trial. Lancet Oncol. 2020;21(7):969-977.