Quality-adjusted Progression-free Survival Research Articles

Health-related quality of life and quality-adjusted progression free survival for carfilzomib and dexamethasone maintenance following salvage autologous stem-cell transplantation in patients with multiple myeloma: a randomized phase 2 trial by the Nordic Myeloma Study Group

BackgroundDecisions regarding maintenance therapy in patients with multiple myeloma should be based on both treatment efficacy and health-related quality of life (HRQL) consequences. In the CARFI trial, patients with first relapse of multiple myeloma underwent salvage autologous stem cell transplantation (salvage ASCT) before randomization to carfilzomib-dexamethasone maintenance therapy (Kd) or observation. The primary clinical endpoint was time to progression, which was extended by 8 months by Kd. The aim of this paper is to present the all HRQL endpoints of the CARFI trial including the HRQL effect of Kd maintenance therapy relative to observation. The primary HRQL endpoint was assessed by EORTC QLQ-C30 Summary score (QLQ-C30-sum) at 8 months follow-up. A key secondary HRQL endpoint was quality-adjusted progression-free-survival (QAPFS).MethodsHRQL was assessed with EORTC QLQ-C30, EORTC QLQ-MY20 and FACT/GOG-Ntx at randomization and every second month during follow-up. HRQL data were analyzed with linear mixed effect models until 8 months follow-up. QAPFS per individual was calculated by multiplying progression-free survival (PFS) by two quality-adjustment metrics, the QLQ-C30-sum and EORTC Quality of Life Utility Measure-Core 10 dimensions (QLU-C10D). The QAPFS per treatment group was estimated with the Kaplan-Meier method. P < 0.05 was used for statistical significance, and a between-group minimal important difference of 10 points was interpreted as clinically relevant for the QLQ-C30-sum.Results168 patients were randomized. HRQL questionnaire compliance was 93%. For the QLQ-C30-sum, the difference of 4.62 points (95% confidence interval (CI) -8.9: -0.4, p = 0.032) was not clinically relevant. PFS was 19.3 months for the Kd maintenance group and 16.8 months for the observation group; difference = 2.5 months (95% CI 0.5; 4.5). QAPFS based on the QLQ-C30-sum for the Kd maintenance group was 18.0 months (95% CI 16.4; 19.6) and for the observation group 15.0 months (95% CI 13.5; 16.5); difference = 3.0 months (95% CI 0.8–5.3). QAPFS based on the QLU-C10D for the Kd maintenance group was 17.5 months (95% CI 15.9; 19.2) and 14.0 months (95% CI 12.4; 15.5) for the observation group; difference = 3.5 months (95% CI 1.1–5.9).ConclusionsKd maintenance therapy after salvage ASCT did not adversely affect overall HRQL, but adjustment for HRQL reduced the PFS compared to unadjusted PFS. PFS of maintenance therapy should be quality-adjusted to balance the benefits and HRQL impact.

Quality-adjusted time without symptoms of disease or toxicity and quality-adjusted progression-free survival with niraparib maintenance in first-line ovarian cancer in the PRIMA trial.

Background:The PRIMA phase 3 trial showed niraparib significantly prolongs median progression-free survival (PFS) versus placebo in patients with advanced ovarian cancer (OC) responsive to first-line platinum-based chemotherapy, including those who had tumors with homologous recombination deficiency (HRd). This analysis of PRIMA examined the quality-adjusted PFS (QA-PFS) and quality-adjusted time without symptoms of disease or toxicity (Q-TWiST) of patients on maintenance niraparib versus placebo.Methods:Patients were randomized 2:1 to receive once-daily maintenance niraparib (n = 487) or placebo (n = 246). QA-PFS was defined as the PFS of patients adjusted for their health-related quality of life (HRQoL) prior to disease progression, measured using European Quality of Life Five-Dimension (EQ-5D) questionnaire index scores from the PRIMA trial. Q-TWiST was calculated by combining data on PFS, duration of symptomatic grade ⩾2 adverse events (fatigue or asthenia, nausea, vomiting, abdominal pain, and abdominal bloating) prior to disease progression, and EQ-5D index scores. Analyses used data collected up to the last date of PFS assessment (May 17, 2019).Results:The restricted mean QA-PFS was significantly longer with niraparib versus placebo in the HRd (n = 373) and overall intention-to-treat (ITT; n = 733) populations (mean gains of 6.5 [95% confidence interval; CI, 3.9–8.9] and 4.1 [95% CI, 2.2–5.8] months, respectively). There were also significant improvements in restricted mean Q-TWiST for niraparib versus placebo (mean gains of 5.9 [95% CI, 3.5–8.6] and 3.5 [95% CI, 1.7–5.6] months, respectively) in the HRd and ITT populations.Conclusions:In patients with advanced OC, first-line niraparib maintenance was associated with significant gains in QA-PFS and Q-TWiST versus placebo. These findings demonstrate that niraparib maintenance treatment is associated with a PFS improvement and that treatment benefit is maintained even when HRQoL and/or toxicity data are combined with PFS in a single measure.Trial registration:ClinicalTrials.gov: NCT02655016; trial registration date: January 13, 2016Plain language summaryBackground: In a large clinical trial called PRIMA, patients with advanced cancer of the ovary (ovarian cancer) were given either niraparib (a type of cancer medicine) or placebo (a pill containing no medicine/active substances) after having chemotherapy (another type of cancer medicine). Taking niraparib after chemotherapy is called maintenance therapy and aims to give patients more time before their cancer returns or gets worse than if they were not given any further treatment. In the PRIMA trial, patients who took niraparib did have more time before their cancer progressed than if they took placebo. However, it is important to consider patients’ quality of life, which can be made worse by cancer symptoms and/or side effects of treatment. Here, we assessed the overall benefit of niraparib for patients in PRIMA.Methods: Both the length of time before disease progression (or survival time) and quality of life were considered using two different analyses:● The first analysis was called quality-adjusted PFS (QA-PFS) and looked at how long patients survived with good quality of life.● The second analysis was called quality-adjusted time without symptoms of disease or toxicity (Q-TWiST) and looked at how long patients survived without cancer symptoms or treatment side effects.Results: The PRIMA trial included 733 patients; 487 took niraparib and 246 took placebo. Around half of the patients in both groups had a type of ovarian cancer that responds particularly well to drugs like niraparib – they are known as homologous recombination deficiency (HRd) patients.● When information on quality of life (collected from patient questionnaires) and survival was combined in the QA-PFS analysis, HRd patients who took niraparib had approximately 6.5 months longer with a good quality of life before disease progression than those who took placebo. In the overall group of patients (including HRd patients and non-HRd patients), those who took niraparib had approximately 4 months longer than with placebo.● Using the second analysis (Q-TWiST) to combine information on survival with cancer symptoms and treatment side effects, the HRd patients taking niraparib had approximately 6 months longer without cancer symptoms or treatment side effects (such as nausea or vomiting) than patients taking placebo. In the overall group of patients, those taking niraparib had approximately 3.5 months longer without these cancer symptoms/side effects than patients receiving placebo.Conclusions: These results show that the survival benefits of niraparib treatment remain when accounting for patients’ quality of life. These benefits were seen not only in HRd patients who are known to respond better to niraparib, but in the overall group of patients who took niraparib.

Quality-Adjusted Survival with Ribociclib Plus Fulvestrant Versus Placebo Plus Fulvestrant in Postmenopausal Women with HR±HER2− Advanced Breast Cancer in the MONALEESA-3 Trial

BackgroundMONALEESA-3 demonstrated an overall survival (OS) benefit for ribociclib plus fulvestrant (R+F) in postmenopausal women with hormone receptor (HR) positive, HER2 negative advanced breast cancer (ABC). This study estimated quality-adjusted (QA) survival outcomes for patients receiving R+F vs. placebo (P)+F in MONALEESA-3. MethodsKaplan-Meier OS was partitioned into health states: (1) toxicity (TOX)=time spent with grade 3 –4 adverse events before progression (DP); (2) progression (PROG)=time between DP and death; and (3) time without symptoms or toxicity (TWiST)=time not in TOX or PROG. QA time was calculated by combining estimated mean time in each health state with treatment-group specific health-state utility values estimated using EQ-5D-5L questionnaire. Outcomes included QA progression-free survival (QAPFS), QAOS, and QA TWiST (Q-TWiST). Q-TWiST was calculated with health-state utility values for TOX and PROG defined relative to TWiST. ResultsMean PFS and OS were significantly greater with R+F vs. P+F (difference 0.56 and 0.19 years). Mean time in TOX and TWiST were greater with R+F; mean time in PROG was greater with P+F. QAPFS was 0.45 years (95% CI 0.27 –0.63) greater with R+F than P+F (P <.001). QAOS was numerically greater with R+F vs. P+F (0.16 years, 95% CI 0.07 –0.45, P = .0569). Q-TWiST was 0.23 years greater with R+F (95% CI 0.07 –0.45, P = .0069). In a sensitivity analysis using an estimate of disutility for PROG, the difference in QAOS was 0.23 years (95% CI 0.08 –0.41, P = .0022). ConclusionR+F in postmenopausal women with HR+/HER2- ABC improves QAPFS, resulting in clinically important improvements in Q-TWiST and may improve QAOS.

738P Quality-adjusted time without symptom or toxicity (QA-TWiST) and quality-adjusted progression-free survival (QA-PFS) of first-line (1L) maintenance niraparib in patients with advanced ovarian cancer (OC): Results from the PRIMA trial

The PRIMA/ENGOT-OV26/GOG-3012 (NCT02655016) phase III trial showed niraparib significantly prolongs median PFS vs placebo in patients with advanced OC responsive to 1L platinum (Pt)-based chemotherapy (CT), regardless of biomarker status. This post hoc analysis of PRIMA examined the QA-TWiST and QA-PFS of patients on maintenance niraparib vs placebo.

PCN222 Health Related Quality of Life (HRQoL) Review in Patients with Ovarian Cancer: A Systematic Literature Review (SLR)

HRQoL estimates are essential components of an effectiveness analysis for a new treatment. The purpose of this research was to review the HRQoL measures used in understanding ovarian cancer (OC) treated with poly(ADP) ribose polymerase inhibitors (PARPi). A SLR was conducted using the Population, Intervention, Comparator, Outcome, Study Design (PICOS) model. Cochrane Library, Medline via Embase, and PubMed were searched for articles in English (2012-July 2020) that addressed HRQoL measured by patient reported outcomes in recurrent epithelial ovarian, fallopian tube and primary peritoneal cancers in treatment with PARPis. All countries were included. Six studies met the final criteria for inclusion. Three PARPis (olaparib, niraparib, and rucaparib) were identified that assessed HRQoL. Instruments used were EuroQoL five-dimension scale (EQ-5D), Functional Assessment of Cancer Therapy-Ovarian (FACT-O), Functional Assessment of Cancer Therapy-Ovarian Cancer symptom index (FOSI), Trial Outcomes Index (TOI), and Quality-Adjusted Progression-Free Survival (QAPFS). Niraparib was comparable to placebo when measured via EQ-5D; niraparib and olaparib were comparable to placebo via FOSI; olaparib was comparable to placebo via FACT-O; olaparib was comparable to placebo via TOI. Olaparib (in 2 studies) and rucaparib had longer QAPFS than placebo. There was no single tool or result common across all assessed interventions. Across all indices, olaparib, niraparib, and rucaparib showed mixed results in terms of HRQoL outcomes compared to placebo. Although patients showed improvement in QAPFS with two PARPis their HRQoL did not seem to improve. This could be due to the drugs’ side-effects or method used to measure HRQoL in these studies. To better understand HRQoL and address the unmet needs in recurrent OC patients, additional research using more advanced methodology is needed.

ENGOT-ov54/Swiss-GO-2/MATAO including LOGOS (Low-Grade Ovarian cancer Sub-study): MAintenance Therapy with Aromatase inhibitor in epithelial Ovarian cancer—A randomized, double-blinded, placebo-controlled, multicenter phase III Trial.

TPS5598 Background: The prognosis of advanced epithelial ovarian cancer (OC) is poor with a relapse rate of 75% at 5 years. Some 80% of OC express estrogen receptor (ER). This is the first trial that wants to capitalize on this and prospectively evaluates letrozole, a potent aromatase inhibitor, as initial maintenance treatment for high and low grade OC. Methods: Eligible pts have primary OC, FIGO Stage II-IV with low or high grade serous or endometrioid histology, with (interval) debulking surgery, ECOG-status 0-2, Positivity (≥ 1%) for ER expression, and at least 4 cycles of platinum-based chemotherapy (neoadjuvant allowed). Pts are allowed to undergo concurrent maintenance treatment with bevacizumab and PARP inhibitors. Extensive quality of life (QoL) questionnaires via an App and physical activity measurements by a tracking device as well as G8 geriatric score, ESGO surgery questionnaire, and Charleson Comorbidity Index are routinely assessed. Primary objective is to evaluate the efficacy of letrozole maintenance therapy after standard surgical and chemotherapy treatment as measured by Progression Free Survival (PFS) compared to no maintenance therapy (placebo). Primary outcome is PFS, defined as time from date of first letrozole/placebo administration until date of progression or death by any cause. Stratification for high and low grade histologies and ER measurement is performed via a digital centralized pathology review process. Final analysis will be performed for the whole cohort and for the subgroup of low grade ovarian cancers (LOGOS subprotocol). Secondary objectives and outcomes are overall survival (OS), quality adjusted progression free survival (QAPFS), time to first subsequent treatment (TFST), quality adjusted time without symptoms (TWiST), and health related QoL. Study is designed as international, randomized (1:1 ratio), two-arm, multi-centric, double-blinded, placebo-controlled superiority phase III trial. In total, 528 pts will be randomly assigned to letrozole or placebo for 5 yrs or until unacceptable toxicity, progression of underlying disease, or study discontinuation. Final analysis is planned after 5 years without interval analysis and follow-up is collected for up to 10yr and for the low-grade cohort for up to 12yr. Clinical trial information: NCT04111978.

Patient-centred outcomes and effect of disease progression on health status in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation receiving maintenance olaparib or placebo (SOLO1): a randomised, phase 3 trial

In the phase 3 SOLO1 trial, maintenance olaparib provided a significant progression-free survival benefit versus placebo in patients with newly diagnosed, advanced ovarian cancer and a BRCA mutation in response after platinum-based chemotherapy. We analysed health-related quality of life (HRQOL) and patient-centred outcomes in SOLO1, and the effect of radiological disease progression on health status. SOLO1 is a randomised, double-blind, international trial done in 118 centres and 15 countries. Eligible patients were aged 18 years or older; had an Eastern Cooperative Oncology Group performance status score of 0-1; had newly diagnosed, advanced, high-grade serous or endometrioid ovarian cancer, primary peritoneal cancer, or fallopian tube cancer with a BRCA mutation; and were in clinical complete or partial response to platinum-based chemotherapy. Patients were randomly assigned (2:1) to either 300 mg olaparib tablets or placebo twice per day using an interactive voice and web response system and were treated for up to 2 years. Treatment assignment was masked for patients and for clinicians giving the interventions, and those collecting and analysing the data. Randomisation was stratified by response to platinum-based chemotherapy (clinical complete or partial response). HRQOL was a secondary endpoint and the prespecified primary HRQOL endpoint was the change from baseline in the Functional Assessment of Cancer Therapy-Ovarian Cancer Trial Outcome Index (TOI) score for the first 24 months. TOI scores range from 0 to 100 (higher scores indicated better HRQOL), with a clinically meaningful difference defined as a difference of at least 10 points. Prespecified exploratory endpoints were quality-adjusted progression-free survival and time without significant symptoms of toxicity (TWiST). HRQOL endpoints were analysed in all randomly assigned patients. The trial is ongoing but closed to new participants. This trial is registered with ClinicalTrials.gov, NCT01844986. Between Sept 3, 2013, and March 6, 2015, 1084 patients were enrolled. 693 patients were ineligible, leaving 391 eligible patients who were randomly assigned to olaparib (n=260) or placebo (n=131; one placebo patient withdrew before receiving any study treatment), with a median duration of follow-up of 40·7 months (IQR 34·9-42·9) for olaparib and 41·2 months (32·2-41·6) for placebo. There was no clinically meaningful change in TOI score at 24 months within or between the olaparib and placebo groups (adjusted mean change in score from baseline over 24 months was 0·30 points [95% CI -0·72 to 1·32] in the olaparib group vs 3·30 points [1·84 to 4·76] in the placebo group; between-group difference of -3·00, 95% CI -4·78 to -1·22; p=0·0010). Mean quality-adjusted progression-free survival (olaparib 29·75 months [95% CI 28·20-31·63] vs placebo 17·58 [15·05-20·18]; difference 12·17 months [95% CI 9·07-15·11], p<0·0001) and the mean duration of TWiST (olaparib 33·15 months [95% CI 30·82-35·49] vs placebo 20·24 months [17·36-23·11]; difference 12·92 months [95% CI 9·30-16·54]; p<0·0001) were significantly longer with olaparib than with placebo. The substantial progression-free survival benefit provided by maintenance olaparib in the newly diagnosed setting was achieved with no detrimental effect on patients' HRQOL and was supported by clinically meaningful quality-adjusted progression-free survival and TWiST benefits with maintenance olaparib versus placebo. AstraZeneca and Merck Sharp & Dohme.

Cost-effectiveness of laparoscopic disease assessment in patients with newly diagnosed advanced ovarian cancer

ObjectiveTo determine if laparoscopy is a cost-effective way to assess disease resectability in patients with newly diagnosed advanced ovarian cancer. MethodsA cost-effectiveness analysis from a health care payer perspective was performed comparing two strategies: (1) a standard evaluation strategy, where a conventional approach to treatment planning was used to assign patients to either primary cytoreduction (PCS) or neoadjuvant chemotherapy with interval cytoreduction (NACT), and (2) a laparoscopy strategy, where patients considered candidates for PCS would undergo laparoscopy to triage between PCS or NACT based on the laparoscopy-predicted likelihood of complete gross resection. A microsimulation model was developed that included diagnostic work-up, surgical and adjuvant treatment, perioperative complications, and progression-free survival (PFS). Model parameters were derived from the literature and our published data. Effectiveness was defined in quality-adjusted PFS years. Results were tested with deterministic and probabilistic sensitivity analysis (PSA). The willingness-to-pay (WTP) threshold was set at $50,000 per year of quality-adjusted PFS. ResultsThe laparoscopy strategy led to additional costs (average additional cost $7034) but was also more effective (average 4.1 months of additional quality-adjusted PFS). The incremental cost-effectiveness ratio (ICER) of laparoscopy was $20,376 per additional year of quality-adjusted PFS. The laparoscopy strategy remained cost-effective even as the cost added by laparoscopy increased. The benefit of laparoscopy was influenced by mitigation of serious complications and their associated costs. The laparoscopy strategy was cost-effective across a range of WTP thresholds. ConclusionsPerforming laparoscopy is a cost-effective way to improve primary treatment planning for patients with untreated advanced ovarian cancer.

The effect of age on efficacy, safety and patient-centered outcomes with rucaparib: A post hoc exploratory analysis of ARIEL3, a phase 3, randomized, maintenance study in patients with recurrent ovarian carcinoma

BackgroundIn the phase 3 trial ARIEL3, maintenance treatment with the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib provided clinical benefit versus placebo for patients with recurrent, platinum-sensitive ovarian cancer. Here, we evaluate the impact of age on the clinical utility of rucaparib in ARIEL3. MethodsPatients with platinum-sensitive, recurrent ovarian carcinoma with ≥2 prior platinum-based chemotherapies who responded to their last platinum-based therapy were enrolled in ARIEL3 and randomized 2:1 to rucaparib 600 mg twice daily or placebo. Exploratory, post hoc analyses of progression-free survival (PFS), patient-centered outcomes (quality-adjusted PFS [QA-PFS] and quality-adjusted time without symptoms or toxicity [Q-TWiST]), and safety were conducted in three age subgroups (<65 years, 65–74 years, and ≥75 years). ResultsInvestigator-assessed PFS was significantly longer with rucaparib than placebo in patients aged <65 years (rucaparib n = 237 vs placebo n = 117; median, 11.1 vs 5.4 months; hazard ratio [HR]: 0.33 [95% confidence interval (95% CI) 0.25–0.43]; P < 0.0001) and 65–74 years (n = 113 vs n = 64; median, 8.3 vs 5.3 months; HR 0.43 [95% CI 0.29–0.63]; P < 0.0001) and numerically longer in patients aged ≥75 years (n = 25 vs n = 8; median, 9.2 vs 5.5 months; HR 0.47 [95% CI 0.16–1.35]; P = 0.1593). QA-PFS and Q-TWiST were significantly longer with rucaparib than placebo across all age subgroups. Safety of rucaparib was generally similar across the age subgroups. ConclusionsEfficacy, patient-centered outcomes, and safety of rucaparib were similar between age subgroups, indicating that all eligible women with recurrent ovarian cancer should be offered this therapeutic option, irrespective of age.https://clinicaltrials.gov/ct2/show/NCT01968213.

Patient-Centered Outcomes in ARIEL3, a Phase III, Randomized, Placebo-Controlled Trial of Rucaparib Maintenance Treatment in Patients With Recurrent Ovarian Carcinoma.

PURPOSETo investigate quality-adjusted progression-free survival (QA-PFS) and quality-adjusted time without symptoms or toxicity (Q-TWiST) in a post hoc exploratory analysis of the phase III ARIEL3 study of rucaparib maintenance treatment versus placebo.PATIENTS AND METHODSPatients with platinum-sensitive, recurrent ovarian carcinoma were randomly assigned to rucaparib (600 mg twice per day) or placebo. QA-PFS was calculated as progression-free survival function × the 3-level version of the EQ-5D questionnaire (EQ-5D-3L) index score function. Q-TWiST analyses were performed defining TOX as the mean duration in which a patient experienced grade ≥ 3 treatment-emergent adverse events (TEAEs) or the mean duration in which a patient experienced grade ≥ 2 TEAEs of nausea, vomiting, fatigue, and asthenia. Q-TWiST was calculated as μTOX × TOX + TWiST, with μTOX calculated using EQ-5D-3L data.RESULTSThe visit cutoff was Apr 15, 2017. Mean QA-PFS was significantly longer with rucaparib versus placebo in the intent-to-treat (ITT) population (375 randomly assigned to rucaparib v 189 randomly assigned to placebo; difference, 6.28 months [95% CI, 4.85 to 7.47 months]); BRCA-mutant cohort (130 rucaparib v 66 placebo; 9.37 months [95% CI, 6.65 to 11.85 months]); homologous recombination deficient (HRD) cohort (236 rucaparib v 118 placebo; 7.93 months [95% CI, 5.93 to 9.53 months]); and BRCA wild-type/loss of heterozygosity (LOH) low patient subgroup (107 rucaparib v 54 placebo; 2.71 months [95% CI, 0.31 to 4.44 months]). With TOX defined using grade ≥ 3 TEAEs, the difference in mean Q-TWiST (rucaparib v placebo) was 6.88 months (95% CI, 5.71 to 8.23 months), 9.73 months (95% CI, 7.10 to 11.94 months), 8.11 months (95% CI, 6.36 to 9.49 months), and 3.35 months (95% CI, 1.66 to 5.40 months) in the ITT population, BRCA-mutant cohort, HRD cohort, and BRCA wild-type/LOH low patient subgroup, respectively. Q-TWiST with TOX defined using select grade ≥ 2 TEAEs also consistently favored rucaparib.CONCLUSIONThe significant differences in QA-PFS and Q-TWiST confirm the benefit of rucaparib versus placebo in all predefined cohorts.

POLO: Quality-adjusted (QA) progression-free survival (PFS) and patient (pt)-centered outcomes with maintenance olaparib in pts with metastatic pancreatic cancer (mPaC).

4626 Background: In the Phase III POLO trial (NCT02184195), maintenance olaparib significantly prolonged PFS vs placebo in pts with a germline BRCA1 and/or BRCA2 mutation (gBRCAm) and mPaC (median 7.4 vs. 3.8 months). The aim of maintenance treatment is to extend PFS and survival without compromising health-related quality of life due to adverse events. The duration of time spent without symptoms or toxicities (TWiST) and the QA-PFS were assessed in a post hoc analysis of the POLO trial. Methods: Patients were randomized 3:2 to receive maintenance olaparib (tablets; 300 mg bid) or placebo. Restricted mean (RM)-PFS was calculated by estimating the area under the Kaplan–Meier PFS curve between randomization and 29.8 months after randomization (maximum follow-up for the placebo arm in POLO). Patient-centered outcomes were assessed by QA-PFS (derived from the product of the EQ-5D-5L single-index utility score from randomization to disease progression and RM-PFS) and TWiST (RM-PFS minus time with toxicity after randomization). Results: RM-PFS was significantly longer with olaparib, with a between-treatment difference of 4.8 months ( P=0.009; Table). Over this period, no significant or meaningful differences in mean EQ-5D-5L index were observed between treatment groups. The corresponding mean QA-PFS was significantly longer with olaparib vs placebo. TWiST analysis demonstrated a benefit with olaparib over placebo (Table): between-arm difference, 3.8 months ( P=0.039) for the primary analysis (criteria 1: grade ≥2 nausea, vomiting or fatigue). Sensitivity analysis (criteria 1 plus abdominal pain, diarrhea, decreased appetite or constipation) also revealed a trend toward benefit with olaparib (difference: 3.4 months, P=0.062). Conclusions: Consistent with the primary PFS analysis of the POLO trial, RM-PFS and QA-PFS were significantly longer with maintenance olaparib than with placebo. As demonstrated by the findings of the TWiST analyses, the PFS benefit observed with olaparib in pts with a gBRCAm and mPaC persists even when symptoms of toxicity are considered. Clinical trial information: NCT02184195 . [Table: see text]

Final overall survival (OS) results from SOLO2/ENGOT-ov21: A phase III trial assessing maintenance olaparib in patients (pts) with platinum-sensitive, relapsed ovarian cancer and a BRCA mutation.

6002 Background: SOLO2 (ENGOT ov-21; NCT01874353) showed that maintenance therapy with the PARP inhibitor olaparib in pts with platinum-sensitive relapsed ovarian cancer (PSROC) and a BRCA mutation (BRCAm) led to a statistically significant improvement in median progression-free survival (PFS) of 13.6 months vs placebo (hazard ratio [HR] 0.30). Time to second progression or death significantly improved (Pujade-Lauraine et al Lancet Oncol 2017) and a quality-adjusted PFS benefit was seen (Friedlander et al Lancet Oncol 2018) with maintenance olaparib vs placebo. We report the preplanned final OS analysis for SOLO2. Methods: Pts with PSROC and a BRCAm who had received ≥2 lines of treatment and were in response to their most recent platinum-based chemotherapy received maintenance olaparib (300 mg bid tablets) or placebo. Pts were stratified by response to previous chemotherapy (complete vs partial) and length of platinum-free interval (&gt;6–12 months vs &gt;12 months). OS was a secondary endpoint. The only preplanned OS sensitivity analysis was an OS analysis in the Myriad germline BRCAm subset (Myriad BRAC Analysis test). Results: At final data cut-off (Feb 3, 2020), median follow-up was 65 months in both treatment arms. A long-term treatment benefit was seen with olaparib vs placebo with an OS HR of 0.74 (95% confidence interval [CI] 0.54–1.00) in the full analysis set (FAS; unadjusted for crossover; 38.4% of placebo pts crossed over to a PARP inhibitor) (Table). At 5 years: by Kaplan-Meier estimates, 28.3% of pts in the olaparib arm vs 12.8% of pts in the placebo arm were alive and had still not received subsequent treatment; 42.1% of olaparib pts vs 33.2% of placebo pts were alive. The long-term tolerability profile of olaparib was generally consistent with that reported previously. Conclusions: In the final analysis of SOLO2, maintenance olaparib provided an unprecedented improvement of 12.9 months in median OS vs placebo. This is the first study with olaparib tablets, and the first since Study 19 (NCT00753545), to provide long-term follow-up and final OS data in pts with PSROC and a BRCAm. Clinical trial information: NCT01874353. [Table: see text]

224O - Patient-centred outcomes with maintenance olaparib in newly diagnosed patients with advanced ovarian cancer (OC) and a BRCA mutation in the phase III SOLO1 trial to support the clinical benefit of prolongation of progression-free survival (PFS)

224O - Patient-centred outcomes with maintenance olaparib in newly diagnosed patients with advanced ovarian cancer (OC) and a BRCA mutation in the phase III SOLO1 trial to support the clinical benefit of prolongation of progression-free survival (PFS)

996PD - Patient-centred outcomes with maintenance olaparib in newly diagnosed patients with advanced ovarian cancer (OC) and a BRCA mutation (BRCAm) in the phase III SOLO1 trial to support the clinical benefit of prolongation of progression-free survival (PFS)

996PD - Patient-centred outcomes with maintenance olaparib in newly diagnosed patients with advanced ovarian cancer (OC) and a BRCA mutation (BRCAm) in the phase III SOLO1 trial to support the clinical benefit of prolongation of progression-free survival (PFS)

Cost-effectiveness analysis of laparoscopic disease assessment in ovarian cancer.

5556 Background: Laparoscopic assessment of disease resectability can be useful for treatment planning for patients [pts] with advanced ovarian cancer [OC] but may be associated with added cost. Methods: We performed a cost-effectiveness analysis from a payer perspective to compare (1) a conventional strategy, where standard new pt evaluation was used to assign pts to either primary cytoreduction [PCS] or neoadjuvant chemotherapy with interval cytoreduction [NACT], and (2) an alternative approach, where pts considered candidates for PCS would undergo laparoscopy to evaluate disease resectability using a validated scoring system, who were then triaged to either PCS or NACT based on this evaluation. Diagnostic work-up, surgical and adjuvant treatment, perioperative complications, and progression-free survival [PFS] were included in the model. We derived model parameters from the literature and our institution’s experience with laparoscopic triage. Utility estimates for health states related to primary treatment were assessed prospectively and taken from the literature. Costs were estimated using Medicare reimbursement. Effectiveness was defined in quality-adjusted progression-free life years [QPFLYs]. We performed multiple sensitivity analyses. Results: Under baseline model parameters, the expected cost of treating one pt under the conventional and alternative strategies was $26,539 and $26,653, respectively. The expected quality-adjusted progression-free survival for pts in the conventional and alternative strategies was 0.70 and 0.94 QPFLYs, respectively. The calculated incremental cost-effectiveness was $473.97 per QPFLY saved. The alternative strategy became cost saving if pts found to have resectable disease by laparoscopy underwent cytoreduction during the same procedure. The conventional strategy may be preferred if PCS increased PFS over NACT by ≥5 months. Conclusions: For newly-diagnosed advanced stage OC pts, laparoscopic assessment of disease resectability prior to PCS was a cost-effective strategy. A conventional strategy may be preferred if PCS produced substantially longer PFS. Sensitivity analysis suggests the benefit of utilizing laparoscopic triage is influenced by mitigation of serious perioperative morbidity and associated costs.

PCN295 PATIENT-CENTERED OUTCOMES IN ARIEL3, A PHASE 3, RANDOMIZED, PLACEBO-CONTROLLED STUDY OF RUCAPARIB MAINTENANCE TREATMENT IN PATIENTS WITH RECURRENT OVARIAN CARCINOMA

In ARIEL3, rucaparib (600 mg BID) maintenance treatment significantly improved progression-free survival (PFS) vs placebo in all predefined cohorts. This post hoc exploratory analysis investigated quality-adjusted PFS (QA-PFS) and quality-adjusted time without symptoms or toxicity (Q-TWiST). QA-PFS was calculated as PFS function × EQ-5D index score function. Q-TWiST was calculated as (μTOX × TOX) + TWiST. TOX represents the mean duration with grade ≥3 adverse events (AEs) or grade ≥2 AEs of nausea, vomiting, fatigue, and asthenia only. TWiST represents the mean duration without AEs or symptoms of progression. μTOX represents the standardized mean EQ-5D index score. This analysis utilized the primary efficacy data after unblinding (April 15, 2017, visit cutoff). In the intent-to-treat population, for rucaparib (n=375) vs placebo (n=189): mean (95% confidence interval [CI]) QA-PFS was 12.02 (10.96–13.03) months vs 5.74 (4.98–6.42) months (difference, 6.28 [4.85–7.47] months); mean (95% CI) Q-TWiST adjusting for grade ≥3 AEs was 13.32 (12.11–14.46) months vs 6.44 (5.78–7.18) months (difference, 6.88 [5.71–8.23] months); and mean (95% CI) Q-TWiST adjusting for common grade ≥2 AEs was 13.16 (12.01–14.33) months vs 6.40 (5.75–7.15) months (difference, 6.77 [5.64–8.14] months). In patients with a BRCA mutation (germline, somatic, or origin unknown), for rucaparib (n=130) vs placebo (n=66): mean (95% CI) QA-PFS was 15.28 (13.22–17.45) months vs 5.92 (4.71–7.23) months (difference, 9.37 [6.65–11.85] months); mean (95% CI) Q-TWiST adjusting for grade ≥3 AEs was 16.42 (14.29–18.18) months vs 6.70 (5.49–8.02) months (difference, 9.73 [7.10–11.94] months); and mean (95% CI) Q-TWiST adjusting for common grade ≥2 AEs was 16.24 (14.11–17.95) months vs 6.68 (5.45–8.00) months (difference, 9.56 [6.99–11.81] months). The significant differences in QA-PFS and Q-TWiST confirm the benefit of rucaparib vs placebo in all predefined cohorts.

Quality of life in patients with advanced epithelial ovarian cancer (EOC) randomized to maintenance pazopanib or placebo after first-line chemotherapy in the AGO-OVAR 16 trial. Measuring what matters—patient-centered end points in trials of maintenance therapy

BackgroundHealth-related quality of life (HRQoL) was a secondary end point in AGO-OVAR 16, which randomized 940 patients with EOC after first-line chemotherapy to maintenance pazopanib (PZ) or placebo (P). Additional post hoc analyses were carried out to investigate additional patient-centered end points. Patients and methodsHRQoL was measured with EORTC-QLQ-C30, QLQ-OV28 and EQ-5D-3L. Pre-specified end points included mean differences in HRQoL between treatment arms. Exploratory analyses included quality-adjusted progression-free survival (QAPFS), impact of specific symptoms and progressive disease (PD) on HRQoL and time to second-line chemotherapy. The objective was to provide clinical perspective to the significant median PFS gain of 5.6months with PZ. ResultsThere were statistically significant differences between PZ and P in QLQ-C30 global health status [5.5 points; 95% confidence interval (CI), 0.7–10.4, P=0.024] from baseline to 25months, but not EQ-5D-3L (0.018 points; 95% CI−0.033 to 0.069, P=0.485). The impact of diarrhea was captured in QLQ-OV28 Abdominal/GI-Symptoms scale (8.1 points; 95% CI 3.6–12.5, P=0.001). QAPFS was 386days (95% CI 366–404days) with PZ versus 359days (95% CI 338–379days) with placebo (P=0.052). PD was associated with a decline in HRQoL (P<0.0001). Median time to second-line chemotherapy was 19.7months with PZ and 15.0months with P [hazard ratio (HR) 0.72, 95% CI 0.69–0.86, P=0.0001]. ConclusionsThere were small to no significant mean score differences in global HRQoL and EQ5D-3L between PZ and placebo, respectively, despite the increased toxicity of PZ. Exploratory end points including QAPFS, impact of specific symptoms on HRQoL during treatment and at PD help place the PFS gain with PZ in context and interpret the results. Additional patient-centered end points should be considered in trials of maintenance therapy in EOC beyond mean differences in HRQoL scores alone, to support the benefit to patients of prolongation of PFS. Clinical Trials Registration NumberNCT00866697

Using quality-adjusted progression-free survival as an outcome measure to assess the benefits of cancer drugs in randomized-controlled trials: case of the BOLERO-2 trial.

The aim of this study is to estimate the quality-adjusted progression-free survival (QAPFS) as an effectiveness measure for the treatment arms of the BOLERO-2 trial. For each treatment arm of the trial, QAPFS was estimated by multiplying the overall health utility weights associated with progression-free survival (PFS) (accounting for utility decrements associated with the adverse events of treatments) by the corresponding mean PFS time. Health utility data were obtained from the literature, while mean PFS times were estimated through a survival analysis of the reconstructed individual patient data of the BOLERO-2 trial. PFS (robust mean, (95% robust confidence interval)) was 44.73weeks (41.03; 48.43) for Everolimus+Exemestane and 22.98weeks (19.88; 26.08) for Placebo+Exemestane. The QAPFS (robust mean, (95% robust confidence interval)) for the treatment arms of the trial was 30.09 (27.60; 32.58) for Everolimus+Exemestane and 16.27 (14.07; 18.46) for Placebo+Exemestane, respectively. Using QAPFS as an outcome measure provides a complete picture of the benefit induced by the treatment arms of the BOLERO-2 trial. The benefit of Everolimus+Exemestane over Placebo+Exemestane observed in the trial is maintained in this analysis. The approach and estimates obtained as part of our analysis can serve as a basis for cost effectiveness analyses of the treatment arms of the BOLERO-2 trial.

Cost-effectiveness analysis of everolimus plus exemestane versus exemestane alone for treatment of hormone receptor positive metastatic breast cancer.

Everolimus in combination with exemestane significantly improved progression-free survival compared to exemestane alone in patients previously treated with non-steroidal aromatase inhibitors in the BOLERO-2 trial. As a result, this combination has been approved by the food and drug administration to treat postmenopausal women with hormone receptor positive and HER2 negative metastatic breast cancer. A cost-effectiveness analysis was conducted to determine whether everolimus represents good value for money, utilizing data from BOLERO-2. A decision-analytic model was used to estimate the incremental cost-effectiveness ratio between treatment arms of the BOLERO-2 trial. Costs were obtained from the Center for Medicare Services drug payment table and physician fee schedule. Benefits were expressed as quality-adjusted progression-free survival weeks (QAPFW) and quality-adjusted progression-free years (QAPFY), with utilities/disutilities derived from the literature. Deterministic and probabilistic sensitivity analyses were performed. A willingness to pay threshold of 1-3 times the per capita gross domestic product was adopted, as per the definition of the World Health Organization. The U.S. per capita gross domestic product in 2013 was $49,965; thus, a threshold varying between $49,965 and $149,895 was considered. Everolimus/exemestane had an incremental benefit of 11.88 QAPFW (0.22 QAPFY) compared to exemestane and an incremental cost of $60,574. This translated into an ICER of $265,498.5/QAPFY. Univariate sensitivity analyses showed important variations of the ICER, ranging between $189,836.4 and $530,947/QAPFY. A tornado analysis suggested that the key drivers of our model, by order of importance, included health utility value for stable disease, everolimus acquisition costs, and transition probabilities from the stable to the progression states. The Monte-Carlo simulation showed results that were similar to the base-case analysis. This cost-effectiveness analysis showed that everolimus plus exemestane is not cost-effective compared to exemestane alone. Further research is needed to investigate the cost-effectiveness of the drug combination within sub-groups of the population studied in BOLERO-2.

The cost effectiveness of bevacizumab when added to capecitabine, with or without mitomycin-C, in first line treatment of metastatic colorectal cancer: Results from the Australasian phase III MAX study

BackgroundBased on the clinical data, bevacizumab has been approved in Australia and globally for the treatment of advanced colorectal cancer. However, limited evidence exists for its cost-effectiveness. The purpose of this study was to evaluate the cost effectiveness of adding bevacizumab to capecitabine monotherapy in patients with metastatic colorectal cancer, using data from the prospective economic evaluation conducted alongside the MAX trial. MethodsIndividual patient level data on resource use and progression free survival were prospectively collected in the phase III MAX trial. Resource use data were collected for the period between randomisation and disease progression, and unit costs were assigned from the perspective of the Australian health care funder. Effectiveness was measured in quality adjusted progression free survival years, with utility scores obtained from both the community valued EQ-5D questionnaire and the patient valued UBQ-C questionnaire. Progression free survival was used as a secondary effectiveness measure. ResultsThe addition of bevacizumab to capecitabine monotherapy cost approximately $192,156 (95% confidence interval [CI], $135,619 to $326,894) per quality adjusted progression free survival year gained when using publicly listed pharmaceutical prices and utility values from the EQ-5D questionnaire. This decreased to $149,455 (95% CI, $100,356 to $245,910) when values from the UBQ-C questionnaire were applied. The incremental cost per progression free survival year was $145,059 (95% CI, $106,703 to $233,225). ConclusionsBevacizumab was not found to be cost effective at its listed price, based on results from the MAX trial.