Patient-centered outcomes in the POLO study of active maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer.

BACKGROUND: The phase 3 POLO study demonstrated a significant progression-free survival (PFS) benefit and preserved health-related quality of life (HRQOL) for active maintenance treatment with olaparib vs placebo in patients with metastatic pancreatic cancer and a germline BRCA mutation. Here, we present a post hoc analysis of the patient-centered outcomes: time without significant symptoms of disease progression or toxicity (TWiST) and quality-adjusted TWiST (Q-TWiST). METHODS: Patients were randomized 3:2 to maintenance olaparib (300 mg tablets twice daily) or placebo. Overall survival time was divided into TWiST, toxicity (TOX; time before disease progression with significant symptoms of toxicity), and relapse (REL; time after disease progression until death or censoring). Q-TWiST was the sum of TWiST, TOX, and REL, each weighted by HRQOL utility scores during the relevant health-state period. A base-case and three sensitivity analyses were performed using differing definitions of TOX. RESULTS: In total, 154 patients were randomized (olaparib, n = 92; placebo, n = 62). TWiST was significantly longer for olaparib than placebo in the base-case analysis (14.6 vs 7.1 months; 95% CI, 2.9-12.0; p = .001) and all sensitivity analyses. No statistically significant benefit for Q-TWiST was observed in the base-case analysis (18.4 vs 15.9 months; 95% CI, -1.1 to 6.1; p = .171) or the sensitivity analyses. CONCLUSION: These results support the previous findings that maintenance olaparib significantly improves PFS relative to placebo without compromising HRQOL and demonstrate that the clinically meaningful benefits of olaparib persist even when symptoms of toxicity are considered.

Real-world outcomes for first line next-generation hormonal agents in metastatic prostate cancer: a systematic review.

Aim: This review aims to summarize published evidence on the real-world (RW) outcomes of abiraterone or enzalutamide in first-line metastatic castration-resistant prostate cancer. Materials & methods: Studies reporting on RW effectiveness, safety, economic and/or health-related quality of life outcomes were identified by systematic literature review (2011-2021, incl. Embase®, MEDLINE®) and presented in a qualitative synthesis. Risk of bias was assessed using ROBINS-I or the Molinier checklist. Results: 88 studies (n = 83,427 patients) were included. Median progression-free (40 studies) and overall survival (38 studies) ranged from 3.7 to 20.9 months and 9.8 to 45 months, respectively. Survival, safety and economic outcomes were similar across individual treatments, while limited health-related quality of life evidence suggested improvements with abiraterone. Risk of bias was moderate to high. Conclusion: RW outcomes in first-line metastatic castration-resistant prostate cancer remain poor despite treatment, highlighting an unmet need for new regimens. This review was supported by AstraZeneca and Merck Sharp & Dohme.

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.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: AstraZeneca and Merck Sharp & Dohme.

Cost-effectiveness of olaparib as a maintenance treatment for women with newly diagnosed advanced ovarian cancer and BRCA1/2 mutations in the United States.

OBJECTIVE: This study evaluated the cost-effectiveness of olaparib monotherapy in the first-line maintenance setting vs. surveillance in women with newly diagnosed advanced ovarian cancer and a BRCA1/2 mutation from a US third-party payer perspective. METHODS: A three-state (progression free, progressed disease, and death) partitioned survival model over a 50-year lifetime horizon was developed. Piecewise models were applied to data from the phase III trial SOLO1 to extrapolate survival outcomes. Health state utilities and adverse event disutilities were obtained from literature and SOLO1. Treatment costs, adverse event costs, and medical costs associated with health states were obtained from publicly available databases, SOLO1, and real-world data. Time on treatment was estimated using the data from SOLO1. Incremental costs per quality-adjusted life year (QALY) and life year (LY) gained were estimated. One-way deterministic and probabilistic sensitivity analyses were conducted. RESULTS: Over a lifetime horizon, olaparib was associated with an additional 3.63 LYs and 2.93 QALYs, and an incremental total cost of $152,545 vs. surveillance. Incremental cost per LY gained and per QALY gained for olaparib were $42,032 and $51,986, respectively. The incremental cost-effectiveness ratios remained below $100,000 across a range of inputs and scenarios. In the PSA, the probability of olaparib being cost-effective at a $100,000 per QALY threshold was 99%. CONCLUSIONS: Compared to surveillance, olaparib increases both the LYs and QALYs of women with newly diagnosed advanced ovarian cancer and with a germline or somatic BRCA mutation. Olaparib offers a cost-effective maintenance option for these women from a US third-party payer perspective.

Impact of Nonrandomized Dropout on Treatment Switching Adjustment in the Relapsing-Remitting Multiple Sclerosis CLARITY Trial and the CLARITY Extension Study.

OBJECTIVES: Statistical methods to adjust for treatment switching are commonly applied to randomized controlled trials (RCTs) in oncology. Nevertheless, RCTs with extension studies incorporating nonrandomized dropout require consideration of alternative adjustment methods. The current study used a recognized method and a novel method to adjust for treatment switching in relapsing-remitting multiple sclerosis (MS). METHODS: The Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) RCT evaluated the efficacy of cladribine versus placebo over 96 weeks. Many (but not all) CLARITY participants enrolled in the 96-week CLARITY extension study; placebo-treated patients from CLARITY received cladribine (PP→LL), and cladribine-treated patients were re-randomized to placebo (LL→PP) or continued cladribine (LL→LL). End points were time to first qualifying relapse (FQR) and time to 3-month and 6-month confirmed disability progression (3mCDP, 6mCDP). We aimed to estimate the effectiveness of the LL→PP treatment strategy compared with a counterfactual (unobserved) PP→PP strategy. We applied the commonly used rank-preserving structural failure time model (RPSFTM) and a novel approach that combined propensity score matching (PSM) with inverse probability of censoring weights (IPCW). RESULTS: The RPSFTM resulted in LL→PP versus PP→PP hazard ratios (HRs) of 0.48 (95% confidence interval [CI] 0.36-0.62) for FQR, 0.62 (95% CI 0.46-0.84) for 3mCDP, and 0.62 (95% CI 0.44-0.88) for 6mCDP. The PSM+IPCW resulted in HRs of 0.47 (95% CI 0.38-0.63) for FQR, 0.61 (95% CI 0.43-0.86) for 3mCDP, and 0.63 (95% CI 0.40-0.87) for 6mCDP. CONCLUSIONS: The PSM+IPCW HRs were consistent with those from the RPSFTM, suggesting that the results were not substantially biased by informative dropout, assuming that all relevant confounders were controlled for. There was no statistical evidence of a reduction in the cladribine treatment effect during the extension period.

Cost-effectiveness of adding novel or group 5 interventions to a background regimen for the treatment of multidrug-resistant tuberculosis in Germany.

BACKGROUND: Treatment of multidrug-resistant tuberculosis (MDR-TB) is complex, lengthy, and involves a minimum of four drugs termed a background regimen (BR), that have not previously been prescribed or that have proven susceptible to patient sputum culture isolates. In recent years, promising new treatment options have emerged as add-on therapies to a BR. The aim of this study was to evaluate the long-term costs and effectiveness of adding the novel or group 5 interventions bedaquiline, delamanid, and linezolid to a background regimen (BR) of drugs for the treatment of adult patients with pulmonary multidrug-resistant tuberculosis (MDR-TB), within their marketing authorisations, from a German healthcare cost-effectiveness perspective. METHODS: A cohort-based Markov model was developed to simulate the incremental cost-effectiveness ratio of bedaquiline plus BR, delamanid plus BR, or linezolid plus BR versus BR alone in the treatment of MDR-TB, over a 10-year time horizon. Effectiveness of treatment was evaluated in Quality-Adjusted Life-Years (QALYs) and Life-Years Gained (LYG), using inputs from clinical trials for bedaquiline and delamanid and from a German observational study for linezolid. Cost data were obtained from German Drug Directory costs (€/2015), published literature, and expert opinion. A 3% yearly discount rate was applied. Probabilistic and deterministic sensitivity analyses were conducted. RESULTS: The total discounted costs per-patient were €85,575 for bedaquiline plus BR, €81,079 for delamanid plus BR, and €80,460 for linezolid plus BR, compared with a cost of €60,962 for BR alone. The total discounted QALYs per-patient were 5.95 for bedaquiline plus BR, 5.36 for delamanid plus BR, and 3.91 for linezolid plus BR, compared with 3.68 for BR alone. All interventions were therefore associated with higher QALYs and higher costs than BR alone, with incremental costs per QALY gained of €22,238 for bedaquiline, €38,703 for delamanid, and €87,484 for linezolid, versus BR alone. In a fully incremental analysis, bedaquiline plus BR was the most cost-effective treatment option at thresholds greater than €22,000 per QALY gained. In probabilistic analyses, the probability that bedaquiline plus BR was the most cost-effective treatment strategy at a willingness-to-pay threshold of €30,000 was 54.5%, compared with 22.9% for BR alone, 18.2% for delamanid plus BR, and 4.4% for linezolid. CONCLUSIONS: In Germany, the addition of bedaquiline, delamanid, or linezolid to a BR would result in QALY gains over BR alone. Based on this analysis, bedaquiline is likely to be the most cost-effective intervention for the treatment of MDR-TB, when added to a BR regimen at thresholds greater than €22,000 per QALY.

Cost-Effectiveness Analysis of Adjuvant Olaparib Versus Watch and Wait in the Treatment of Germline BRCA1/2-Mutated, High-Risk, HER2-Negative Early Breast Cancer in Sweden.

INTRODUCTION: This study evaluated the cost effectiveness of adjuvant olaparib versus watch and wait (WaW) in patients with germline breast cancer susceptibility gene 1/2 (gBRCA1/2)-mutated, high-risk, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer (eBC), previously treated with neoadjuvant or adjuvant chemotherapy, from a Swedish healthcare perspective. METHODS: A five-state (invasive disease-free survival [IDFS], non-metastatic breast cancer [non-mBC], early-onset mBC, late-onset mBC, death) semi-Markov state transition model with a lifetime horizon was developed. Transition probabilities were informed by data from the Phase III OlympiA trial, supplemented with data from additional studies in BRCA-mutated, HER2-negative mBC. Health state utilities were derived via mapping of OlympiA data and supplemented by literature estimates. Treatment, adverse events and other medical costs were extracted from publicly available Swedish sources. Incremental cost per life-year (LY) and quality-adjusted life-year (QALY) gained were estimated. Costs and outcomes were discounted at 3% annually. One-way deterministic and probabilistic sensitivity analyses (PSA) were conducted. RESULTS: Over a lifetime horizon, adjuvant olaparib was associated with an additional 1.50 LYs and 1.22 QALYs, and incremental cost of 471,156 Swedish krona (SEK) versus WaW (discounted). The resulting ICER was 385,183SEK per QALY gained for olaparib versus WaW. ICERs remained below 1,000,000SEK across a range of scenarios, and were consistent across subgroups (hormone receptor [HR]-positive/HER2-negative and triple-negative breast cancer [TNBC]). In PSA, the probability of olaparib being cost effective at 1,000,000SEK per QALY was 99.8%. CONCLUSIONS: At list price, adjuvant olaparib is a cost-effective alternative to WaW in patients with gBRCA1/2-mutated, high-risk, HER2-negative eBC in Sweden.

Survival Extrapolation Incorporating General Population Mortality Using Excess Hazard and Cure Models: A Tutorial.

BACKGROUND: Different parametric survival models can lead to widely discordant extrapolations and decision uncertainty in cost-effectiveness analyses. The use of excess hazard (EH) methods, which incorporate general population mortality data, has the potential to reduce model uncertainty. This review highlights key practical considerations of EH methods for estimating long-term survival. METHODS: Demonstration of methods used a case study of 686 patients from the German Breast Cancer Study Group, followed for a maximum of 7.3 y and divided into low (1/2) and high (3) grade cancers. Seven standard parametric survival models were fit to each group separately. The same 7 distributions were then used in an EH framework, which incorporated general population mortality rates, and fitted both with and without a cure parameter. Survival extrapolations, restricted mean survival time (RMST), and difference in RMST between high and low grades were compared up to 30 years along with Akaike information criterion goodness-of-fit and cure fraction estimates. The sensitivity of the EH models to lifetable misspecification was investigated. RESULTS: In our case study, variability in survival extrapolations was extensive across the standard models, with 30-y RMST ranging from 7.5 to 14.3 y. Incorporation of general population mortality rates using EH cure methods substantially reduced model uncertainty, whereas EH models without cure had less of an effect. Long-term treatment effects approached the null for most models but at varying rates. Lifetable misspecification had minimal effect on RMST differences. CONCLUSIONS: EH methods may be useful for survival extrapolation, and in cancer, EHs may decrease over time and be easier to extrapolate than all-cause hazards. EH cure models may be helpful when cure is plausible and likely to result in less extrapolation variability. HIGHLIGHTS: In health economic modeling, to help anchor long-term survival extrapolation, it has been recommended that survival models incorporate background mortality rates using excess hazard (EH) methods.We present a thorough description of EH methods with and without the assumption of cure and demonstrate user-friendly software to aid researchers wishing to use these methods.EH models are applied to a case study, and we demonstrate that EHs are easier to extrapolate and that the use of the EH cure model, when cure is plausible, can reduce extrapolation variability.EH methods are relatively robust to lifetable misspecification.

Association between event-free survival and overall survival after neoadjuvant treatment for non-small cell lung cancer: a systematic review and meta-analysis.

BACKGROUND: We wanted to evaluate if event-free survival (EFS) is a reliable surrogate for overall survival (OS) in patients with resectable non-small cell lung cancer (r-NSCLC) receiving neoadjuvant therapy. We conducted a systematic literature review and meta-analysis to investigate the statistical association between EFS and OS. RESEARCH DESIGN AND METHODS: Electronic databases were searched on 30 July 2021 to identify sources reporting both EFS and OS data in patients with stage I-IIIB r-NSCLC receiving neoadjuvant therapy. Correlation and regression analyses evaluated the association between the effect of treatment on EFS and OS using log-hazard ratios (HRs). Sources in which the entire population had epidermal growth factor receptor mutations were excluded from the analyses. RESULTS: We identified 74 sources, of which 8 reported EFS and OS HRs from randomized controlled trials. Based on these, we found a positive linear correlation and a strong association between EFS and OS log-HRs (weighted Pearson's correlation coefficient r = 0.864; 95% confidence interval 0.809-0.992; P = 0.006; random-effects meta-regression, R2 = 0.777). CONCLUSIONS: We found a strong association between treatment effects for EFS and OS, indicating that improvements in EFS are likely to be predictive of improvements in OS. EFS may therefore be a reliable surrogate for OS after neoadjuvant therapy in r-NSCLC.

Indirect treatment comparison of olaparib and talazoparib in germline BRCA-mutated HER2-negative metastatic breast cancer.

Aim: Two poly(ADP-ribose) polymerase (PARP) inhibitors olaparib and talazoparib are approved for patients with germline BRCA-mutated (gBRCAm) HER2-negative metastatic breast cancer. Methods: A Bayesian fixed-effects indirect treatment comparison (ITC) analysis was performed to simulate the comparative efficacy (primary outcome of progression-free survival [PFS]) and safety of PARP inhibitor monotherapy. Results: ITC of data from the OlympiAD (olaparib) and EMBRACA (talazoparib) studies suggested no significant difference in efficacy (PFS) between olaparib and talazoparib. However, there were differences in specific adverse events; patients receiving olaparib had a higher rate of nausea and vomiting, while those receiving talazoparib had a higher rate of alopecia and anemia. Discussion: These data support the benefit of the PARP inhibitor class in gBRCAm HER2-negative metastatic breast cancer.

Real-world treatment patterns and outcomes in small-cell lung cancer: a systematic literature review.

BACKGROUND: Small-cell lung cancer (SCLC) accounts for 12-15% of lung cancers and is associated with poor survival outcomes and high symptom burden. This study employed a broad, systematic search strategy and timeframe to identify evidence on real-world treatment patterns and outcomes for SCLC outside the USA, including understanding sub-populations such as extensive-stage (ES) or limited-stage (LS) disease. METHODS: Databases (MEDLINE, Embase, and EBM reviews) were searched for journal articles published in the English language between 1 January 2000-1 March 2020 and supplemented by hand searching of conference abstracts and posters presented at conferences between 1 January 2016-1 March 2020 reporting real-world treatment outcomes in patients with SCLC. A targeted clinical guideline review was also completed. RESULTS: One-hundred studies provided quantitative data; 57 were available as full-text articles, whilst the remaining 43 were presented as abstracts or posters. The majority (80 studies, 80%) of included studies reported treatment in the first-line setting, where platinum-based chemotherapy and chemoradiotherapy was the most commonly used treatment strategy, in line with current treatment guidelines in SCLC. First-line treatments were found to have a high response rate; however, most patients relapsed early. No studies reported treatment or outcomes with immune-oncology therapies. Second-line treatment options were very limited, and primarily consisted of either re-treatment with first-line regimen or topotecan, but the prognosis for these patients remained poor. Outcomes were particularly poor amongst those with ES or relapsed disease vs. LS disease. CONCLUSIONS: SCLC treatment patterns and short survival outcomes have remained constant over the previous 20 years. Due to the search timeframe, none of the studies identified reported on the impact of recently approved immune-oncology therapies in SCLC. Further data is needed on the impact of immunotherapies on treatment patterns and real-world outcomes in SCLC.

Population-adjusted indirect treatment comparison of maintenance PARP inhibitor with or without bevacizumab versus bevacizumab alone in women with newly diagnosed advanced ovarian cancer.

BACKGROUND: In patients with newly diagnosed ovarian cancer, bevacizumab and poly(ADP-ribose) polymerase (PARP) inhibitors, alone or in combination, have shown benefit as maintenance treatment following platinum-based chemotherapy. However, no trials have compared a PARP inhibitor plus bevacizumab versus a PARP inhibitor, or a PARP inhibitor versus bevacizumab. We performed an unanchored population-adjusted indirect treatment comparison to estimate the relative efficacy and safety of maintenance treatments for newly diagnosed advanced ovarian cancer. METHODS: Analyses were performed using aggregate data from the PRIMA trial and patient-level data from a subset of patients from the PAOLA-1 trial that met surgery and staging eligibility criteria of PRIMA. Propensity weights were used to match baseline characteristics of the PAOLA-1 subset to those of the PRIMA population. Analysis was performed in overall (biomarker-unselected) and homologous recombination repair deficiency (HRD)-positive populations. RESULTS: A total of 595/806 (266/387 HRD-positive) PAOLA-1 patients were included. After matching, the effective sample size for PAOLA-1 was 532 (242 HRD-positive). Maintenance olaparib plus bevacizumab reduced the risk of disease progression or death by 43% [hazard ratio (HR) 0.57; 95% confidence interval (CI): 0.47-0.69] versus niraparib and by 40% (HR 0.60; 95% CI: 0.49-0.74) versus bevacizumab in the biomarker-unselected population and by 43% (HR 0.57; 95% CI: 0.41-0.79) and 60% (HR 0.40; 95% CI: 0.29-0.55), respectively, in the HRD-positive population. Progression-free survival (PFS) benefits of maintenance niraparib and bevacizumab arms were comparable in the biomarker-unselected population (HR 1.07; 95% CI: 0.87-1.32); however, niraparib showed a 30% reduced risk compared with bevacizumab (HR 0.70; 95% CI: 0.51-0.97) in the HRD-positive population. CONCLUSIONS: In biomarker-unselected and HRD-positive patients, combination treatment with olaparib plus bevacizumab as maintenance treatment improves PFS for women with newly diagnosed advanced ovarian cancer compared with either bevacizumab or niraparib alone. Results are hypothesis generating and could guide randomised trial design.

Cost-effectiveness of olaparib versus routine surveillance in the maintenance setting for patients with BRCA-mutated advanced ovarian cancer after response to first-line platinum-based chemotherapy in Singapore.

OBJECTIVE: To evaluate the cost-effectiveness of olaparib as a maintenance treatment versus routine surveillance (RS) in patients with BRCA mutated (BRCAm) advanced ovarian cancer (OC) following response to first-line platinum-based chemotherapy in Singapore. METHODS: A 4-health state partitioned survival model was developed to simulate the lifetime (50 years) incremental cost-effectiveness ratio (ICER) of olaparib versus RS from a healthcare payer perspective. Progression-free survival, time to second disease progression, and overall survival were estimated using SOLO-1 data and extrapolated beyond the trial period using parametric survival models. Any patient who remained progression-free at year 7 was assumed to be no longer at risk of progression. Mortality rates were based on all-cause mortality, adjusted based on BRCA1/2 mutation. Health state utilities and adverse event frequencies were from SOLO-1. Drug costs were from local public healthcare institutions. Healthcare resource usage and costs were from local clinician input and publications. A 3% discount rate was applied to costs and outcomes. Deterministic and probabilistic sensitivity analyses (PSA) were performed to assess the robustness of results. RESULTS: The base-case analysis of olaparib maintenance therapy versus RS resulted in an ICER of Singapore dollar (SGD) 19,822 per quality-adjusted life-year (QALY) gained. The ICER was most sensitive to variations in the discount rate. PSA demonstrated that olaparib had an 87% probability of being cost-effective versus RS at a willingness-to-pay of SGD 60,000 per QALY gained. CONCLUSION: Olaparib has a high potential of being a cost-effective maintenance treatment versus RS for patients with BRCA1/2m advanced OC after response to first-line chemotherapy in Singapore.

Exploring the Impact of Treatment Switching on Overall Survival from the PROfound Study in Homologous Recombination Repair (HRR)-Mutated Metastatic Castration-Resistant Prostate Cancer (mCRPC).

BACKGROUND: In oncology trials, treatment switching from the comparator to the experimental regimen is often allowed but may lead to underestimating overall survival (OS) of an experimental therapy. OBJECTIVE: This study evaluates the impact of treatment switching from control to olaparib on OS using the final survival data from the PROfound study and compares validated adjustment methods to estimate the magnitude of OS benefit with olaparib. PATIENTS AND METHODS: The primary population from PROfound (Cohort A) was included, alongside two populations approved for treatment with olaparib by the European Medicines Agency and US Food and Drug Administration: BRCAm and Cohort A+B (excluding the PPP2R2A gene). Five methods were explored to adjust for switching: excluding or censoring patients in the control arm who receive subsequent olaparib, Rank Preserving Structural Failure Time Model (RPSFTM), Inverse Probability of Censoring Weights, and Two-Stage Estimation. RESULTS: The RPSFTM was considered the most appropriate approach for PROfound as the results were robust to sensitivity analysis testing of the common treatment effect assumption. For Cohort A, the final OS hazard ratio reduced from 0.69 (95% CI 0.5-0.97) to between 0.42 (0.18-0.90) and 0.52 (0.31-1.00) for olaparib versus control, depending on the RPSFTM selected. Median OS reduced from 14.7 months to between 11.73 and 12.63 months for control. CONCLUSIONS: The magnitude of the statistically significant (P < 0.05) survival benefit of olaparib versus control observed in Cohort A of PROfound is likely to be underestimated if adjustment for treatment switching from control to olaparib is not conducted. The RPSFTM was considered the most plausible method, although further development and validation of robust methods to estimate the magnitude of impact of treatment switching is needed.

Population-adjusted indirect treatment comparison of the SOLO1 and PAOLA-1/ENGOT-ov25 trials evaluating maintenance olaparib or bevacizumab or the combination of both in newly diagnosed, advanced BRCA-mutated ovarian cancer.

BACKGROUND: In the absence of randomised head-to-head trials, we conducted a population-adjusted indirect treatment comparison (PA-ITC) of phase III trial data to evaluate the relative efficacy and safety of maintenance olaparib and bevacizumab alone and in combination in patients with newly diagnosed, advanced ovarian cancer and a BRCA mutation (BRCAm). METHODS: An unanchored PA-ITC was performed on investigator-assessed progression-free survival (PFS) data. Individual patient data from SOLO1 (olaparib versus placebo) and from BRCA-mutated patients in PAOLA-1/ENGOT-ov25 (olaparib plus bevacizumab versus placebo plus bevacizumab) were pooled. Each arm of PAOLA-1 was weighted so that key baseline patient characteristics were similar to the SOLO1 cohort. Analyses were performed in patients with complete baseline data. Weighted Cox regression analysis was used to estimate the comparative efficacy of different maintenance therapy strategies, supplemented by weighted Kaplan-Meier analyses. RESULTS: Data from SOLO1 patients (olaparib, n = 254; placebo, n = 126) were compared with data from BRCA-mutated PAOLA-1 patients (olaparib plus bevacizumab, n = 151; placebo plus bevacizumab, n = 71). Adding bevacizumab to olaparib was associated with a numerical improvement in PFS compared with olaparib alone (hazard ratio [HR] 0.71; 95% confidence interval [CI] 0.45-1.09). Statistically significant improvements in PFS were seen with olaparib alone versus placebo plus bevacizumab (HR 0.48; 95% CI 0.30-0.75), olaparib plus bevacizumab versus placebo (0.23; 0.14-0.34), and placebo plus bevacizumab versus placebo (0.65; 0.43-0.95). CONCLUSIONS: Results of this hypothesis-generating PA-ITC analysis support the use of maintenance olaparib alone or with bevacizumab in patients with newly diagnosed, advanced ovarian cancer and a BRCAm.

Assessing the Long-Term Effectiveness of Cladribine vs. Placebo in the Relapsing-Remitting Multiple Sclerosis CLARITY Randomized Controlled Trial and CLARITY Extension Using Treatment Switching Adjustment Methods.

OBJECTIVES: Treatment switching adjustment methods are often used to adjust for switching in oncology randomized controlled trials (RCTs). In this exploratory analysis, we apply these methods to adjust for treatment changes in the setting of an RCT followed by an extension study in relapsing-remitting multiple sclerosis. METHODS: The CLARITY trial evaluated cladribine tablets versus placebo over 96 weeks. In the 96-week CLARITY Extension, patients who received placebo in CLARITY received cladribine tablets; patients who received cladribine tablets in CLARITY were re-randomized to placebo or cladribine tablets. End points were time to first qualifying relapse (FQR) and time to 3- and 6-month confirmed disability progression (3mCDP, 6mCDP). We aimed to compare the effectiveness of cladribine tablets with placebo over CLARITY and the extension. The rank-preserving structural failure time model (RPSFTM) and iterative parameter estimation (IPE) were used to estimate what would have happened if patients had received placebo in CLARITY and the extension versus patients that received cladribine tablets and switched to placebo. To gauge whether treatment effect waned after the 96 weeks of CLARITY, we compared hazard ratios (HRs) from the adjustment analysis with HRs from CLARITY. RESULTS: The RPSFTM resulted in an HR of 0.48 [95% confidence interval (CI) 0.36-0.62] for FQR, 0.62 (95% CI 0.46-0.84) for 3mCDP and 0.62 (95% CI 0.44-0.88) for 6mCDP. IPE algorithm results were similar. CLARITY HRs were 0.44 (95% CI 0.34-0.58), 0.60 (95% CI 0.41-0.87) and 0.58 (95% CI 0.40-0.83) for FQR, 3mCDP and 6mCDP, respectively. CONCLUSIONS: Treatment switching adjustment methods are applicable in non-oncology settings. Adjusted CLARITY plus CLARITY Extension HRs were similar to the CLARITY HRs, demonstrating significant treatment benefits associated with cladribine tablets versus placebo. FUNDING: EMD Serono, Inc. (a business of Merck KGaA, Darmstadt, Germany).

A Critical Appraisal and Recommendations for Cost-Effectiveness Studies of Poly(ADP-Ribose) Polymerase Inhibitors in Advanced Ovarian Cancer.

BACKGROUND: Ovarian cancer is the fifth leading cause of cancer death in women in the US. With poly(ADP-ribose) polymerase (PARP) inhibitors having shown promising results in ongoing trials, there is interest in better understanding their economic value. OBJECTIVE: This study aimed to review and evaluate the quality of published cost-effectiveness analyses (CEAs), and provide recommendations for CEAs in this setting. METHODS: A systematic literature review of the MEDLINE and EMBASE databases was conducted in June 2019 to identify CEAs of PARP inhibitors in treating advanced ovarian cancer from peer-reviewed journals and conferences. Key information from the identified publications were extracted and reviewed. The quality of full-text studies was assessed using the Quality of Health Economic Studies instrument. Recommendations for future CEAs were developed based on the findings from the literature review. RESULTS: Eighteen CEAs (five in full texts) met the inclusion criteria. Most adopted a US healthcare or societal perspective. The majority of the studies did not clearly display the economic model structure. No studies reported the validation of model projections based on internal or external data. Surrogate outcomes such as incremental costs per progression-free life-year gained were the most common outcomes reported. The majority of studies drew their conclusions based on surrogate outcomes, even with no theoretical or empirical threshold for cost effectiveness. All five full-text studies included some type of sensitivity or scenario analyses. The key drivers of the incremental cost-effectiveness ratio were treatment duration, effects, and costs, health utility, and prevalence of BRCA mutations. CONCLUSION: In the existing CEAs for PARP inhibitors, there were uncertainties and challenges leading to variation in quality. We provided recommendations to improve consistency and quality of CEAs in this setting, which will help to better understand the value of PARP inhibitors, improve decision making, and reduce potential misallocation of resources.

Patient-reported outcomes in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer receiving olaparib versus chemotherapy in the OlympiAD trial.

BACKGROUND: The phase III OlympiAD study (NCT02000622) showed a statistically significant progression-free survival benefit with olaparib versus chemotherapy treatment of physician's choice (TPC) in patients with a germline BRCA mutation and human epidermal growth factor receptor 2-negative metastatic breast cancer. From this study, we report the effect of olaparib on health-related quality of life (HRQoL). METHODS: Patients were randomised 2:1 to olaparib monotherapy (300 mg twice daily) or single-agent TPC. The primary HRQoL end-point was mean change from baseline in the two-item global health status/QoL score determined from patient-completed European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item module (EORTC QLQ-C30) questionnaires and assessed using a mixed model for repeated measures. Symptoms and functioning domains, best overall response and time to deterioration of QoL were also evaluated. RESULTS: Overall questionnaire compliance rates were 93.2% for olaparib and 76.3% for TPC. Between-treatment global health status/QoL comparison showed a significant improvement in the olaparib arm versus the TPC arm, with mean change of 3.9 (standard deviation 1.2) versus -3.6 (2.2), a difference of 7.5 points (95% confidence interval [CI]: 2.48, 12.44; P = 0.0035). A higher proportion of patients in the olaparib arm showed a best overall response of 'improvement' in global health status/QoL (33.7% vs 13.4%). Median time to global health status/QoL deterioration was not reached in olaparib patients and was 15.3 months for TPC patients (hazard ratio: 0.44 [95% CI: 0.25, 0.77]; P = 0.004). For EORTC QLQ-C30 symptoms and functioning subscales, only nausea/vomiting symptom score was worse in the olaparib arm than in the TPC arm (across all visits compared with baseline). CONCLUSION: HRQoL was consistently improved for patients treated with olaparib, compared with chemotherapy TPC.