Olaparib Not Cost-effective as Maintenance Therapy for Platinum-sensitive, BRCA1/2 Germline-mutated Metastatic Pancreatic Cancer
Tarun Mehra , Judith E. Lupatsch, Thibaud Kössler, Konstantin Dedes, Alexander Reinhard Siebenhüner, Roger von Moos, Andreas Wicki, Matthias E. Schwenkglenks
Abstract
Objective
To assess the cost-effectiveness and budget impact of olaparib as a maintenance therapy in platinum-responsive, metastatic pancreatic cancer patients harboring a germline BRCA1/2 mutation, using the Swiss context as a model.
Methods
Based on data from the POLO trial, published literature and local cost data, we developed a partitioned survival model of olaparib maintenance including full costs for BRCA1/2 germline testing compared to FOLFIRI maintenance chemotherapy and watch-and-wait. We calculated the incremental cost-effectiveness ratio (ICER) for the base case and several scenario analyses and estimated 5-year budget impact.
Results
Comparing olaparib with watch-and wait and maintenance chemotherapy resulted in incremental cost-effectiveness ratios of CHF 2,711,716 and CHF 2,217,083 per QALY gained, respectively. The 5-year costs for the olaparib strategy in Switzerland would be CHF 22.4 million, of which CHF 11.4 million would be accounted for by germline BRCA1/2 screening of the potentially eligible population. This would amount to a budget impact of CHF 15.4 million (USD 16.9 million) versus watch-and-wait.
Introduction
Pancreatic cancer accounts for 3% of all cancer diagnoses in the United States and for 7% of cancer deaths [1]. Over half the cases are diagnosed at an advanced stage which has a 5-year overall survival rate of less than 10% [2]. Treatment options for advanced disease are limited. In the PRODIGE4/ACCORD11 trial, platinum-based chemotherapy with FOLFIRINOX demonstrated the best results so far in this setting. Median overall survival (OS) was 11.1 months with FOLFIRINOX compared to 6.8 months with gemcitabine, albeit at the price of substantially higher toxicity [3]. FOLFIRINOX has been the first-line standard of care since, along with gemcitabine and nab-paclitaxel [4], with very limited therapy options thereafter. Olaparib is a poly-ADP-ribose-polymerase (PARP) inhibitor, which acts by impeding homologous recombination repair (HRR) of damaged DNA strands. In patients with constitutionally impaired HRR mechanisms due to germline mutations of genes such as BRCA1 or BRCA2, further inhibition of HRR leads to cell death. Germline BRCA1/2 (gBRCA1/2) mutational prevalence in patients with pancreatic cancer ranges from 3.8% to 7%, with the higher value probably due to a higher percentage of patients with Ashkenazi descendency in the examined populations [5–7]. The POLO trial examined the effect of olaparib maintenance therapy in BRCA1/2-germline-mutated patients with metastatic pancreatic adenocarcinoma that had not progressed under first-line platinum-based chemotherapy. The trial reported a significant increase in PFS, a median of 7.4 months in the treatment group versus 3.8 months in the placebo group [7]. However, the trial showed no overall survival or quality of life improvement [7–9]. Antitumor activity of olaparib in advanced pancreatic cancer has been confirmed in a real-life setting via the open-label phase II TAPUR basket trial [10].
Methods
A list of abbreviations can be found in S1 File (S1 Table in S1 File).
We developed a partitioned survival model (S1 Methods in S1 File) comprising three health states representing stable disease pre-progression, progressive disease and death. The model compared an olaparib maintenance strategy with two standard of care comparator strategies involving maintenance chemotherapy with FOLFIRI (representing a possible clinical standard) and a watch-and-wait approach (essentially mimicking the comparator arm in the POLO trial). With a focus on practical relevance, the latter was regarded as the main comparator strategy for which a full set of uncertainty analyses was performed. Fig 1 is a graphical description of the treatment strategies (Fig 1). The olaparib maintenance strategy included costs for gBRCA1/2 testing of all pancreatic cancer patients evaluated for eligibility. Outcomes included quality-adjusted life-years (QALYs), costs in total and by category, and incremental cost-effectiveness ratios. The time horizon was 10 years, essentially implying life-long for the patient population under study. Costs and effects were discounted by 3% per year in the base case and evaluated against a hypothetical willingness-to-pay (WTP) threshold of Swiss francs (CHF) 100,000 per QALY gained. All costs were assessed from the Swiss statutory health insurance perspective. We calculated incremental cost-effectiveness ratios (ICER) comparing all three strategies.
Results
Cost-effectiveness analysis
Of the three strategies, watch-and-wait was the least expensive with total expected per-patient costs of CHF 110,445 (USD 121,490), followed by the FOLFIRI maintenance strategy with CHF 136,252 (USD 149,877) and the olaparib strategy with CHF 251,657 (USD 276,823) (including BRCA1/2 testing of all potentially eligible patients). The watch-and-wait and maintenance strategies both yielded 1.43 QALYs and the olaparib strategy 1.48. The maintenance strategy was absolutely dominated by the watch-and-wait strategy, given the same amount of QALYs but higher costs. Comparing olaparib with watch-and-wait resulted in an ICER of CHF 2,711,716 (USD 2,982,888) per QALY gained. Comparing FOLFIRI-maintenance with olaparib resulted in an ICER of CHF 2,217,083 (USD 2,438) per QALY gained. Without testing the whole potentially eligible cohort for gBRCA1/2 mutations, the last-mentioned ICERs would change substantially to CHF 814,167 (USD 895,583) and CHF 3128,732 (USD 350,605) per QALY gained, respectively.
Discussion
Cost-effectiveness
Using a modelling approch including the entire expected costs of olaparib treatment in patients with metastatic pancreatic cancer led to ICERs of olaparib which were far from cost-effective when considering standard willingness-to-pay thresholds. Including total costs for gBRCA1/2-testing of all potentially eligible patients and assuming no overall survival differences between the olaparib and watch-and-wait strategies led to an ICER of around CHF 2,700,000 per QALY gained. This result was driven by substantially higher costs of the olaparib strategy and, on the effectiveness side, by an only small gain in quality-adjusted lifetime, emerging from a longer time lived without progression and shorter time lived with progression. Small changes in the analysis strategy impacted the ICER values rather substantially as our scenario analyses demonstrated. However, ICERs usually regarded as cost-effective were not reached. Even when simulating considerably lower costs for gBRCA1/2 testing of of less than tenfold the Swiss market price, leading to an decrease of the incremental cost in comparison to the watch-and-wait strategy by two-thirds, the cost-per-QALY gained still amounted to over USD 800,000 (Table 2 scenario 6).
Citation: Mehra T, Lupatsch JE, Kössler T, Dedes K, Siebenhüner AR, von Moos R, et al. (2024) Olaparib is not cost-effective as maintenance therapy for platinum-sensitive, BRCA1/2 germline-mutated metastatic pancreatic cancer. PLoS ONE 19(4): e0301271. https://doi.org/10.1371/journal.pone.0301271
Editor: Qi Chen, University of Kansas Medical Center, UNITED STATES
Received: December 7, 2023; Accepted: March 13, 2024; Published: April 4, 2024
Copyright: © 2024 Mehra et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: We used pre-published open-access data from the POLO trial. All additional data (cost, outcome and epidemiological data) are publihed in the supplementary file.
Funding: This study was partially funded by the Swiss Study Group for Clinical Cancer Research (SAKK, Schweizerische Arbeitsgemeinschaft für Klinische Krebsforschung). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. There was no additional external funding received for this study”.
Competing interests: All authors have read the journal’s policy and the authors of this manuscript have the following competing interests. AW: no conflicts of interest for this article AS: no conflicts of interest for this article KD: no conflicts of interest for this article TK: no conflicts of interest for this article JL: no conflicts of interest for this article MS: unrelated to the present work, research funding from AbbVie, Biogen, Bristol Myers Squibb, Merck Sharpe & Dohme, Mundipharma, Novartis, and Roche via employment institution; personal fees from Sandoz RvM: consultancy fees from Astra Zeneca, Eili Lilly, Gilead Science, GlaxoSmithKline, Merck, MSD, Novartis, Pierre Fabre, Pharmamar, Sanofi and Vifor. Travel grants from Pierre Fabre, Takeda TM: no conflicts of interest for this article This study was partially funded by Swiss Study Group for Clinical Oncological Research (SAKK, Schweizerische Arbeitsgemeinschaft für Klinische Krebsforschung). This does not alter our adherence to PLOS ONE policies on sharing data and materials.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0301271#abstract0
