Pharmacoeconomics of novel pharmacotherapies in triple-negative breast cancer

ABSTRACT

Introduction

Triple-negative breast cancer (TNBC) represents the most aggressive breast cancer subtype carrying unfavorable clinical outcomes. Although traditionally chemotherapy has represented the only systemic treatment option available, novel drugs have changed the treatment landscape, granting approval by regulatory agencies worldwide, while determining new economic struggles on health systems for their high prices.

Areas covered

In this review, we provided a comprehensive analysis of pharmacoeconomic studies of drugs recently approved in the early and advanced settings of TNBC.

Expert opinion

Novel systemic treatment options redefined the therapeutic algorithms for TNBC by establishing new paradigms, based on substantial clinical benefits. Pembrolizumab and olaparib in the curative setting portend high value, as shown with the use of value frameworks, resulting in cost-effective interventions. In the metastatic setting, new drugs have demonstrated mixed improvements in patient-centric end-points, resulting often in interventions unlikely to have good value for money. We believe that cost-effectiveness alone is not a metric to inform the opportunity to invest on new interventions, while the intrinsic value of medicines should be the driver of the decisions. We endorse a patient-centric priority setting that can ensure health system sustainability, to timely deliver innovative cancer care to all in need and positively impact on population health.

KEYWORDS:

• Antibody–drug conjugates
• breast cancer
• cost-effectiveness
• cost–utility
• immunotherapy
• PARP inhibitors
• pharmacoeconomics
• triple-negative breast cancer

1. Review objectives

With the increasing prevalence of tumor malignancies, cancer care imposes an enormous economic burden on societies and health-care systems [1]. Breast cancer (BC) is the most diagnosed cancer worldwide and a primary contributor to morbidity, disability, and mortality of women, yielding a significant economic and financial impact. In 2020, it accounted for 11.7% of all cancer diagnoses [2], with 2.3 million new cases and 685.000 deaths worldwide [3]. As a result, BC alone accounts for the highest overall costs for care among solid and hematologic tumors [1]. In 2019, BC alone was the cause of a loss of 20.6 million disability-adjusted life years (DALYs), corresponding to a welfare loss of nearly 0.1% of the Gross Domestic Product (GDP), namely 88 USD billion-dollar, on the global scale [4]. Cost of inaction in breast cancer control results in economic losses, due, for example, to productivity loss. Investing in high-value health interventions for breast cancer control can portend population health benefits, cognizant that the cost of inaction is counted as lives lost. Investing in high value does mean assuring sustainability and value for money. In 2020, $29.8 billion of expenditures took place in the US alone for BC, accounting for cancer-attributable costs of health-care services and treatment prescriptions [1].

Triple-negative breast cancer (TNBC) represents 15–25% of all breast cancers [5] and is defined by the lack of hormone receptors and no overexpression of human epidermal growth factor receptor 2 (HER2), as per the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines [6,7]. TNBC is the subtype exhibiting the most adverse clinical outcomes [8] and tends to occur at younger ages compared to HER2-positive and hormone receptors-positive BC [9,10]. As a result, TNBC has the highest economic impact on societies, including in terms of productivity loss, family planning, and on subsequent generations (i.e. the risk of orphanage), having broader societal implications [11]. Historically, a lack of predictive biomarkers for targeted therapies has limited the systemic treatment options for TNBC, represented primarily by conventional chemotherapies. Indeed, from an economic standpoint, expenditures in terms of direct costs for active oncologic treatments represent only 5–30% of the total amount [12–14] and a restricted portion of the overall direct costs for TNBC care [15,16]. Nevertheless, previous pharmacoeconomic analyses reflected clinical scenario in which traditional chemotherapies were the only treatments available, not reflecting modern scenarios. In this paper, we analyzed the pharmacoeconomics of novel drugs for TNBC, with the aim to better understand the trade-off between their cost and the net clinical benefit conveyed.

1.1. The changing landscape of systemic therapeutic options for patients with triple-negative breast cancer

In the last few years, novel therapeutic options, namely immune-oncology (IO) agents, targeted therapies, and antibody–drug conjugates (ADC), have been granted approval by regulatory agencies and have been introduced among multiple guideline recommendations, therefore weighing significantly on the overall health expenditure for breast cancer.

Atezolizumab. Based on the results of the IMpassion130 trial [17] (NCT02425891) (Table 1), the anti-PD-L1 atezolizumab has been established as the first IO agent approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in 2019, in combination with nab-paclitaxel, for PD-L1-positive tumors (PD-L1 ≥1% by VENTANA SP142) in the first-line setting of metastatic TNBC (mTNBC) [27,28]. An FDA review of the landscape of clinical trials with atezolizumab in the space of mTNBC has later generated uncertainties on the true benefit of atezolizumab in mTNBC, being the original approval contingent on the results of IMpassion131 (i.e. atezolizumab plus paclitaxel) – that did not confirm an improvement of OS [18]. As a result, a voluntary withdrawal of the indication was provided by the pharmaceutical company in the US [29,30]

Table 1. Pivotal trials of novel pharmacotherapy options in early and advanced TNBC.

Trial (NCT identifier) and Reference	Setting	Population	Phase	No. of patients (randomization)	Experimental arm	Control arm	Primary end-points (key secondary)	Results	ESMO MCBS
IMpassion130 (NCT02425891) [17]	Metastatic	1 L mTNBC	III	451 (1:1)	Atezolizumab plus nab-paclitaxel	Nab-paclitaxel	PFS; OS	PFS: 7.2 vs. 5.5, HR 0.80, CI 95% 0.69 to 0.92; P = 0.002 (ITT); 7.5 vs. 5.0 months, HR 0.62, 95% CI 0.49 to 0.78; P < 0.001 (PD-L1 positive). OS: 21.0 vs. 18.7 months, HR 0.87, 95% CI 0.75, 1.02; P = 0.0770 (ITT); 25.4 vs. 17.9 months, HR 0.67, 95% CI 0.53, 0.86 [not formally tested per prespecified testing hierarchy] (PD-L1+)	3
IMpassion131 (NCT03125902) [18]	Metastatic	1 L mTNBC	III	651 (2:1)	Atezolizumab plus paclitaxel	Paclitaxel	PFS (OS)	PFS: 6.0 vs. 5.7 months, HR 0.82, 95% CI 0.60–1.12; P = 0.20 (PD-L1 positive) OS: 22.1 vs. 28.3 months, HR 1.11, 95% CI 0.76–1.64 (PD-L1 positive)	NA
KEYNOTE-355 (NCT02819518) [19]	Metastatic	1 L mTNBC	III	882 (2:1)	Pembrolizumab plus chemotherapy (nab-paclitaxel, paclitaxel, or gemcitabine – carboplatin)	Chemotherapy (nab-paclitaxel, paclitaxel, or gemcitabine – carboplatin)	PFS; OS	PFS: 9.7 vs. 5.6 months, HR 0.66, 95% CI, 0.50 to 0.88 (CPS-10); 7.6 vs. 5.6 months, HR 0.75; 95% CI, 0.62 to 0.91 (CPS-1) 7.5 vs. 5.6 months, 0.82; 95% CI, 0.70 to 0.98 (ITT) OS: 23.0 vs. 16.1, HR 0.73, 95% CI 0.55 to 0.95; P = 0.0185 (CPS-10) 17.6 vs. 16.0, HR 0.86, 95% CI 0.72 to 1.04; P = 0.1125 (CPS-1) 17.2 vs. 15.5 months, HR 0.89; 95% CI, 0.76 to 1.05 [significance not tested]	3
KEYNOTE-522 (NCT03036488) [20,21]	Early	Stage II or III TNBC	III	1174 (2:1)	Neoadjuvant Pembrolizumab plus paclitaxel and carboplatin, followed by pembrolizumab or placebo plus cyclophosphamide- either doxorubicin or epirubicin; pembrolizumab for 27 weeks after surgery	Neoadjuvant paclitaxel and carboplatin, followed by pembrolizumab or placebo plus cyclophosphamide- either doxorubicin or epirubicin	pCR; EFS	pCR (primary analysis): 64.8% vs. 51.2%; Δ 13.6%; 95% CI, 5.4 to 21.8; P < 0.001 EFS (at 36 months): 84.5% vs. 76.8%, HR 0.63, 95% CI, 0.48 to 0.82; P < 0.001	A
OlympiAD (NCT02000622) [22]	Metastatic	gBRCAm and HER2-negative mBC who had received ≤2 lines of chemotherapy for mBC	III	302 (2:1)	Olaparib	Capecitabine, vinorelbine, or eribulin	PFS (OS)	PFS: 7.0 vs. 4.2 months, HR 0.58, 95% CI 0.43 to 0.80; P < 0.001 OS: 19.3 vs. 17.1 months, HR 0.90, 95% CI 0.66 to 1.23, P = 0.513 [subgroup analysis] Prior treatments: 1 L HR 0.51, 95% CI 0.29 to 0.90; 2 L-3 L HR 1.13, 0.79 to 1.64 Hormone receptors status: TNBC HR 0.93, 0.62 to 1.43; HR + 0.86, 0.55 to 1.36 Prior platinum: yes: 0.83, 0.49 to 1.45; no: 0.91, 0.64 to 1.33	4
EMBRACA(NCT01945775) [23]	Metastatic	gBRCAm and HER2-negative mBC	III	431 (2:1)	Talazoparib	Capecitabine, eribulin, gemcitabine or vinorelbine	PFS (OS)	PFS: 8.6 vs. 5.6 months, HR 0.54, 95% CI 0.41 to 0.71; P < 0.001 OS: 19.3 vs. 19.5 months, HR 0.848, 95% CI 0.670 to 1.073, P = 0.17 [Subgroup analysis] Hormone receptor status: TNBC HR 0.899 (0.634 to 1.276); HR+ HR 0.827 (0.597 to 1.143)	4
OlympiA (NCT02032823) [24]	Early	gBRCAm and HER2-negative high-risk TNBC: T2 or higher or N1 or higher treated with adjuvant; not pCR treated with neoadjuvant HR+: N2 treated with adjuvant chemotherapy; not pCR and CPS+EG score of 3 or higher in neoadjuvant chemotherapy	III	1836 (1:1)	Adjuvant Olaparib for 52 weeks	Placebo	IDFS (DDFS; OS)	IDFS (at 4 years): 86.5% vs. 79.1%, HR 0.607 (0.476–0.771) [TNBC 87.3% vs 79.4%, HR 0.591 (0.450–0.772)] DDFS (at 4 years): 82.7% vs. 75.4%. HR 0.628, 95% CI 0.504–0.779 [TNBC 83.1% vs 75.2%, HR 0.620 (0.487–0.787)] OS (at 4 years): 89.8% vs. 86.4%, HR 0.678, 95% CI 0.503 to 0.907 [TNBC 90.1% vs. 86.3%, HR 0.640 (0.459–0.884)]	A
ASCENT (NCT02574455) [25]	Metastatic	Relapsed or refractory metastatic triple-negative breast cancer (all patients received previous taxanes)	III	529 (1:1)	Sacituzumab govitecan	Capecitabine, eribulin, gemcitabine, or vinorelbine	PFS (OS)	PFS: 5.6 vs. 1.7 months, HR 0.41, 95% CI, 0.32 to 0.52, P < 0.001 OS: 12.1 vs. 6.7 months, HR 0.48, 95% CI, 0.38 to 0.59, P < 0.001	4
DESTINY-Breast04 (NCT03734029) [26]	Metastatic	HER2-low mBC who had received one or two previous lines of chemotherapy	III	557 (2:1) [494 HR+, 63 HR-]	Trastuzumab deruxtecan	Capecitabine, eribulin, gemcitabine, nab-paclitaxel, paclitaxel	PFS (OS)	PFS: ITT: 9.9 vs. 5.1 months, HR 0.50; P < 0.001; TNBC: 8.5 vs. 2.9 months, HR 0.46; 95% CI, 0.24 to 0.89 OS: ITT: 23.4 vs. 16.8 months, HR 0.64, P = 0.001; TNBC: 18.2 vs. 8.3 months, HR 0.48, 95% CI, 0.24 to 0.95	4 (in the ITT)

Notes: Keys: ESMO MCBS, magnitude of clinical benefit scale of the European Society for Medical Oncology; Nr: number; 1 L: first-line; mTNBC: metastatic triple-negative breast cancer; PFS: progression-free survival; OS: overall survival; HR: hazard ratio; CI: confidence interval; ITT: intention to treat; PD-L1: programmed death-ligand 1; pCR: pathological complete response; EFS: event-free survival; gBRCAm: germinal BRCA-mutated; HR: hormone receptors; CPS: clinical-pathologic stage; EG: estrogen receptor status (E), grade (G); IDFS: invasive disease-free survival; DDFS: distant disease-free survival; mBC: metastatic breast cancer; NA: not applicable.

Pembrolizumab. Pembrolizumab was the second IO agent approved for mTNBC by the FDA [31] and EMA [32] in November 2020–2021, based on the results of the KEYNOTE-355 trial [19]. Pembrolizumab added to chemotherapy is a treatment option in the first line, as recommended in the oncology guidelines of the European Society for Medical Oncology (ESMO) and of the NCCN for mTNBC with tumor expression of PD-L1 (combined positive score [CPS] ≥10) [33,34]. More recently, the addition of pembrolizumab to the standard neoadjuvant chemotherapy and continued as a single agent after surgery adjuvant was granted approval in the early TNBC (eTNBC) setting by the FDA [35] and EMA [36] following the results of the KEYNOTE-522 trial [20,21]. The addition of pembrolizumab showed to reduce the risk of cancer recurrence and is now deemed a standard of care for patients with high-risk eTNBC [33].

PARP inhibitors. The class of therapeutics inhibiting the DNA-repair associated protein PARP was recently included in therapeutic algorithms for HER2-negative breast cancer in patients with deleterious germline BRCA1 and BRCA2 alterations, both for mTNBC and high-risk eTNBC. Olaparib and talazoparib are recommended for mTNBC by the NCCN [33] and ESMO [34] guidelines following the results of the OlympiAD and the EMBRACA trials, in which they demonstrated to improve progression-free survival PFS but not overall survival (OS) [22,23]. In addition, 1-year of adjuvant Olaparib has demonstrated OS benefit in the OlympiA trial [24], granting regulatory approval by the FDA and EMA in 2022 [37,38].

Antibody drug-conjugates. ADCs have demonstrated efficacy in patients with pretreated mTNBC, having a commonly dismal prognosis [39]. Sacituzumab-govitecan (SG), a trophoblast cell surface antigen 2 (TROP2)-directed ADC with a topoisomerase I (TOPO1) targeting payload – recently approved by the FDA [40] and EMA [41] following results of the ASCENT trial [25]. In ASCENT, SG demonstrated both PFS and OS benefits when compared to standard chemotherapy [42,43].

The HER2-directed ADC trastuzumab-deruxtecan (TDXd) is conjugated to a TOPO1-inhibitor payload: it was granted approval by the FDA in August 2022 [44] and pending final decision by the EMA [45] for HER2-low metastatic BCs, including mTNBC. The decision was based on the results of the pivotal DESTINY-Breast04 trial, which showed a PFS and OS benefit [44,45].

Although a significant benefit in clinical outcomes is expected to take place from recent therapeutical approvals, given their high marketed cost, it becomes necessary to evaluate their impact on economic outcomes, to assure sustainability in the delivery of health impact.

2. Study selection

We conducted a literature research interrogating PubMed/MEDLINE and the Cochrane Library. To assist retrieval of pharmacoeconomics studies on new therapeutic drugs for TNBC, the following research strategy was applied: ‘Triple Negative Breast Cancer’ AND ‘cost*’ OR ‘economic*’ AND ‘drug*’ OR ‘treatment*’ OR ‘therapy,’ including the corresponding MeSH terms. We retrieved 161 articles, which were further filtered excluding articles in non-English language and studies not published within 5 years since December 2022, resulting in 129 articles. Manual screening of abstract and full texts was further performed to exclude studies on non-pharmaceutical interventions and reviews/meta-analyses, resulting in 10 articles deemed to be eligible for this review. To further enrich our literature research for novel drugs recently approved in TNBC, an additional research was performed in PubMed/MEDLINE and the Cochrane Library using the mapped terms ‘Sacituzumab Govitecan’ OR ‘Pembrolizumab’ OR ‘Atezolizumab’ OR ‘Olaparib’ OR ‘Talazoparib’ OR ‘Trastuzumab Deruxtecan,’ including only studies examining economic outcomes: cost-benefit, cost-effectiveness, cost–utility, cost-minimization analysis, budget impact, cost opportunity, value for money. Additional eight articles were retrieved.

3. Economic burden

3.1. Immunotherapy

Several pharmacoeconomic studies evaluated the use of IO agents in the first-line mTNBC setting (Table 2). A first study on atezolizumab was based on a Markov chain to model the disease course and applied clinical data from the IMpassion130 trial, to estimate the incremental cost-effectiveness ratio (ICER) for both the PD-L1-positive and PD-L1-undetermined population [46]. The analysis estimated an ICER of $196,073 and $281,448 per quality-adjusted life years (QALY) in two populations, respectively. The authors deemed atezolizumab to be cost-effective for the PD-L1-positive but not PD-L1-untested population from a US perspective of willingness to pay (WTP) threshold of $200,000 [46]. One additional study reported favorable cost-effectiveness results from the use of atezolizumab in the PD-L1-positive population [60]. Nevertheless, several models reported prohibitive high ICERs, accounting for costs of the drug, procedures of administration, and management of adverse events, performed by Li et al. (ICER: $361,218/QALY, in the US) [47], Phua et al. (ICER: $324,550/QALY in Singapore) [51], Weng et al. (ICER $229,359/QALY in the US and $72,971/QALY in China) [50], Chisaki et al. (¥30,208,143/QALY in Japan with a WTP of ¥15,000,000/QALY) [48], and Liu et al. (¥118,146/QALY in China) [49]. All the studies from non-US perspectives deemed atezolizumab a non-cost-effective therapeutic option, mostly because of the high cost of the IO drug: ICER was most sensitive to variations in the cost of atezolizumab. The studies showed that ICER could still be close to US$ 80000–100,000/QALY with up to 90% discount of atezolizumab. The addition of atezolizumab to nab-paclitaxel was unlikely to represent good value for money.

Table 2. Studies conducted to assess the pharmacoeconomic profile of novel pharmacotherapies in TNBC.

Study (Country)	Reference	Setting	Population	Drug	Control arm	Clinical data resource	Economic model structure	Life Years	QALY	ICER (WTP)	Cost-effective?
Wu et al. (U.S.)	[46]	Metastatic	A: PD-L1 status unknown B: PD-L1 positive	Atezolizumab + nab-paclitaxel	Nab-paclitaxel	IMpassion130 trial	Markov model	A: Δ 0.632; B: Δ 1.324	A: Δ 0.371; B: Δ 0.762	A: $281,448; B: $196,073 (WTP $200,000)	A: No; B: Yes
Li et al. (U.S)	[47]	Metastatic	A: ITT B: PD-L1 positive	Atezolizumab + nab-paclitaxel	Nab-paclitaxel	IMpassion130 trial	Markov model	Δ 0.24	Δ 0.16	A: $786,131; B: $361,218	No
Chisaki et al. (Japan)	[48]	Metastatic	PD-L1 positive	Atezolizumab + nab-paclitaxel	Nab-paclitaxel	IMpassion130 trial	Markov model	2.04 vs. 1.49	1.12 vs. 0.82	¥30,208,143/QALY (WTP ¥15,000,000)	No
Liu et al. (China)	[49]	Metastatic	A: ITT B: PD-L1 positive C: PD-L1 negative	Atezolizumab + nab-paclitaxel	Nab-paclitaxel	IMpassion130 trial	Partitioned survival model	A: 2.606 vs. 1.87; B: 3.101 vs. 1.836; C: 2.316 vs. 1.907	A: 1.724 vs. 1.297; B: 2.035 vs. 1.259; C: 1.548 vs. 1.34	A: $176,056/QALY B: $118,146/QALY C: $323,077/QALY	No
Weng et al. (China and U.S.)	[50]	Metastatic	A: ITT B: PD-L1 positive	Atezolizumab + nab-paclitaxel	Nab-paclitaxel	IMpassion130 trial	Markov model	A: 1.87 LYs vs. 1.29; B: 2.2 vs. 1.144	A: 1.41 vs. 0.99; B: 1.66 vs. 0.88	(U.S.) A: $331,996.89; B: US$229,359.88 (WTP $150,000/QALY) (China) A: $106,339.26; B: $72,971.88 (WTP $29,383/QALY)	No
Phua et al. (Singapore)	[51]	Metastatic	PD-L1 positive	Atezolizumab + nab-paclitaxel	Nab-paclitaxel	IMpassion130 trial	Partitioned-survival model	Δ 0.636	Δ 0.361	$324,550/QALY	No
Huang et al. (U.S)	[52]	Metastatic	PD-L1 positive	Pembrolizumab + chemotherapy (carboplatin + gemcitabine; or paclitaxel; or nab-paclitaxel)	Chemotherapy (carboplatin + vemcitabine; or paclitaxel; or nab-paclitaxel)	KEYNOTE-355	Partitioned-survival model	Δ 0.84	Δ 0.70	$182,732/QALY ($200,000)	Yes
Fasching et al. (US)	[53]	Early setting	High-risk early-stage (N+; and/or T2 or more)	Pembrolizumab + neoadjuvant chemotherapy (carboplatin + paclitaxel, followed by cyclophosphamide + epirubicin/doxorubicin) + adjuvant pembrolizumab for 27 weeks	Neoadjuvant chemotherapy (carboplatin + paclitaxel, followed by cyclophosphamide + epirubicin/doxorubicin)	KEYNOTE-522	Multistate transition model	Δ 3.37	Δ 2.90	$27,285/QALY	Yes
Saito et al. (Japan)	[54]	Metastatic	gBRCAm HER2-negative	Olaparib monotherapy with BRCA1/2 mutation profiling	Standard chemotherapy without BRCA1/2 mutation profiling (capecitabine; vinorelbine; eribulin)	OlympiAD trial	Markov model	Δ 0.040	Δ 0.037	$131,047/QALY ($89,286)	No
Olry de Labry Lima et al. (Spain)	[55]	Metastatic	gBRCAm HER2-negative A: patients pretreated with anthracyclines, taxanes and hormone therapy; B: patients pre-treated with capecitabine	A and B: Talazoparib	A: Capecitabine; B: Eribulin	EMBRACA trial	Partitioned survival model	Δ 0.35	Δ 0.23	A: 252,420.04€/QALY; B: 259,609.36€/QALY	No
Schwarz et al. (Germany)	[56]	Metastatic	gBRCAm HER2-negative	Talazoparib	Capecitabine, vinorelbine, gemcitabine, or eribuline	EMBRACA trial	Partitioned survival model	Δ 0.32	Δ 0.22	€323,932/QALY	No
Zettler et al. (US)	[57]	Early setting	Hypotetical 42-year-old women with BRCA-mutated, early-stage breast cancer	Olaparib	Placebo	OlympiA trial	Decision-analytic model (not specified)	Δ 1.21	Δ 1.15	$114,500/QALY ($150,000)	Yes
Chen et al. (China and U.S.)	[58]	Metastatic	mTNBC	Sacituzumab govitecan	Eribulin, vinorelbin, capecitabine, gemcitabine	ASCENT trial	Partitioned survival model [Markov model to validate the results]	Δ 0.41	Δ 0.35	Chinese perspective: ¥6375856/QALY [Markov Model ¥640,7626/QALY]; (WTP ¥72,447 to ¥217,341/QALY) U.S. perspective: $501123/QALY [Markov model $507,416/QALY]; (WTP $100,000 to $150,000/QALY)	No
Lang et al. (U.S.)	[59]	Metastatic	A: HER2-low mBC B: HER2-low HR+ mBC	Trastuzumab deruxtecan	Capecitabine, vinorelbine, gemcitabine, eribuline, paclitaxel, nab-paclitaxel	DESTINY-Breast04 trial	Partitioned survival model	/	Δ A: 0.451 Δ B: 0.470	A: [ICUR] $346,571.8/QALY B: [ICUR] $337,789.4/QALY (WTP $150,000/QALY)	No

Note: Keys: QALY: quality-adjusted life years; ICER: incremental cost-effectiveness ratio; WTP: willingness to pay; PD-L1: programmed death-ligand 1; ITT: intention to treat; mBC: metastatic breast cancer; ICUR: incremental cost–utility ratio.

We identified a single economic evaluation on pembrolizumab in the first-line [52]: based on KEYNOTE-355 and focusing on the PD-L1 CPS ≥ 10% population, the authors applied a partitioned-survival model pondered accounting for all treatment-related costs. They estimated an extra 0.70 QALY from the addition of pembrolizumab to chemotherapy, with an ICER of $182,732/QALY. This value was deemed cost-effective in light of the US-WTP threshold [52]. A network meta-analysis compared the outcomes in the PD-L1 CPS ≥ 10 population of the IMpassion130 and KEYNOTE-355, using nab-paclitaxel as a chemotherapy backbone [61]. The economic evaluation showed that pembrolizumab brings an additional 0.73 life-years (LY) and 0.61 QALY over atezolizumab, with an ICER of $44,157/QALY [61]. Therefore, the authors reported that pembrolizumab might bring better value for money [61].

For eTNBC, the addition of Pembrolizumab to chemotherapy in the neoadjuvant-adjuvant setting [53] resulted in an additional 3.37 LY and 2.90 QALYs, with an incremental cost per QALY of $27,285. From a US third-party payer perspective, IO in this setting was deemed cost-effective [53].

3.2. PARP-inhibitors

In the mTNBC setting, three cost-effectiveness analyses on PARP inhibitors were conducted in Japan, Spain, and Germany [54–56].

The Japanese-based cost-effectiveness analysis took into account the costs for BRCA1 and BRCA2 molecular profiling and subsequent treatment with olaparib [54]. Based on a Markov chain, and applying a time frame of 5 years, the authors found only a modest incremental benefit (ICER: $131,047/QALY). Based on the WTP of Japan, olaparib was considered not cost-effective in comparison with standard chemotherapy [54].

An evaluation of the monetary impact of talazoparib was conducted from the health-care perspective of the Spanish National Health System [55]. The authors conducted an incremental cost–utility ratio (ICUR) assessment using QALY as the utility measure and developed a partitioned survival model considering the survival data of the EMBRACA trial [23]. They found that the use of talazoparib compared to capecitabine, vinorelbine, or eribulin, resulted in a health-care expenditure of €252,420.04 for an additional QALY gained: talazoparib was not favored in the cost–utility analysis [55].

Another pharmacoeconomic study of talazoparib was conducted from the German health-care system standpoint [56]. With a price of €6810.82 for one cycle of treatment and assuming a WTP of up to 3-time the German GDP per capita/QALY, the authors estimated an ICER of €223,246 per life-year (LY) and €323,932 per QALY gained, concluding talazoparib was not a cost-effective treatment option at the current marketed price in Germany [56].

An evaluation of direct costs for adverse events (AEs) of Olaparib and Talazoparib compared to chemotherapy was performed by McCrea et al. [62]. The authors retrieved all grade ≥ 3 AEs from the OlympiAD and EMBRACA trials, assessed AE-related unit cost pondered to 2018 prices, and estimated the per-patient cost from the US third-party payer and German health insurance system perspective. Within-study comparison, authors found the AEs cost for olaparib/treatment of physician’s choice (TPC) to be $3,151/€320 and $4,595/€380, respectively, and for talazoparib/TPC to be $7,939/€807 and $4,345/€433 [62]. The authors implemented an indirect treatment comparison (ITC) model, resulting in AEs cost of $4,291/€404 for olaparib and $10,719/€904 for talazoparib, concluding olaparib provided a lower AEs cost compared to TPC and talazoparib [62].

In the early setting of disease, an economic evaluation for adjuvant olaparib [57] based on OlympiA trial [24] and assuming a cost for olaparib of $14,523 per month estimated an ICER of $114,500/QALY. The authors concluded that adjuvant olaparib is a cost-effective option from a US perspective [57].

3.3. Antibody–drug conjugates

We identified an economic analysis for sacituzumab govitecan (SG) performed from the Chinese and US health-care payer perspectives [58], based on the ASCENT trial [63]. SG compared to chemotherapy resulted in an additional 0.35 QALY, with an ICER of 92.4037$/QALY and 49.4479$/QALY in China and in the US, respectively. On a one-way sensitivity analysis, the cost of SG had the greatest impact on ICER, and thus the authors concluded that SG is not a cost-effective treatment option considering the current WTP of both China and the US [58].

A single economic evaluation was conducted for T-DXd for HER2-low breast cancer using a Markov model in a time frame of 15 years [59]. Retrieving clinical data from the DESTINY-Breast04 [26], the authors found a 0.789 QALYs gain, resulting in an ICER of $197,355/QALY, thus reckoning TDXd not as a cost-effective option in the United States [59], for the current high cost.

3.4. Economic impact of new cancer medicines for TNBC under a modern perspective

Despite historically the cost driven by systemic anticancer drugs in TNBC has been limited [64], around 5–30% of the total TNBC care expenditures [12–14], a change in such paradigm is currently taking place. New cancer drugs have a major weight on health budgets. While novel treatment options are expected to improve the clinical outcomes of TNBC patients, they will continue to impact the economic burden on health-care systems and, in some settings, lead to financial distress for patients through out-of-pocket expenses. However, a surge in economic expenditures to account for novel high-priced drugs could translate into a drop in resources expended for other contributing factors of direct costs; indeed, costs for hospitalization and emergency admissions account for most of the direct cost for breast cancer in the metastatic setting, factors that could be limited by better and more tolerable treatment options [15,16]. At the same time, given the fact that TNBC tends to affect younger women, treatments that could delay time to disease progressions, cumulative comorbidities and premature deaths can significantly lower the indirect economic burden by preventing loss of productivity – a factor infrequently measured in pharmacoeconomic models of cost-effectiveness. Nonetheless, with the ongoing approval of highly marketed-priced drugs, a crucial issue to tackle is represented by the predictable increase in the treatment offer disparity between high- and low-income countries, in which price tags of novel drugs will surmount the financial capacities of health-care systems. In this setting, price negotiations toward fair pricing may be key to enhance sustainability, while other strategies can be applied to enable the uptake of high-value innovative drugs, with agreements that are based on pay-for-performance or other managed entry agreements [4].

There is no doubt that breast cancer represents a global public health problem, with high-impact implications from inactions in prevention and control. Investing toward areas of high value is key to delivering population health benefits. Sustainability of health systems and efficiency in health budgeting for cancer cannot be reached by using cost-effectiveness to drive all the decisions in cancer care. Cancer is a priority area of the health agenda, and expenditure must be prioritized to deliver benefits for all in need. Comprehensive econometric evaluations can inform the decision to reimburse and the coverage to apply, including cost-effectiveness thresholds, but encompassing the multidimensional evaluations for patient-centric health care is not a mere question of health budgeting.

4. Conclusion

In recent years, several novel therapeutic options became available for the treatment of early and metastatic TNBC, demonstrating noteworthy improvements in clinical outcomes. Nevertheless, these new pharmacotherapies are burdened by a considerably superior ‘pharmacoeconomic toxicity,’ which could further exacerbate the financial burden of oncologic drugs on health-care systems and undermine the sustainability of cancer care and timely access to innovation. To compensate for such a demand, regulatory authorities must wisely and accurately select new therapeutic options considering the impact they have on patient-centric endpoints, including overall survival and quality of life. On the contrary, health-technology assessment bodies must deal with the skyrocketing prices of new cancer drugs, to deliver coverage and reimbursement decisions based on the pharmacoeconomic metrics and ensure equitability and priority access to potentially vulnerable populations. In our analysis, we identified limited value for money for the majority of the recently approved new drugs for mTNBC, due to their high costs despite conveying significant OS benefits in some cases. While a trade-off based on cost-effectiveness thresholds is not universally applied for decision-making, metrics of value for money, such as the ICER, are taken into great consideration in the exercise of priority-setting, especially in the context of resource constraints. As a result, efforts must be directed toward the improvement of affordability of new high-value cancer medicines to offer priority access to patients with major needs, ensuring fair pricing, and maintaining the trigger for innovation, based on multidimensional, patient-centric value frameworks.

5. Expert opinion

TNBC represents a clinically unmet need, given the adverse oncological outcomes with a higher risk of disease recurrence in the early setting and higher risk of mortality in the metastatic disease, as compared with other subtypes of BC. TNBC prognosis depends both on the intrinsic aggressiveness of the disease and on the limited treatment options available.

In early setting, new drugs capable of reducing the risk of recurrence and improving overall survival are key to tackle such an adverse prognosis. Tailoring patients with biomarker-informed approaches can increase the benefits portended by new therapies and improve cost-effectiveness. The demonstration of meaningful benefits in survival end-points with pembrolizumab for high-risk eTNBC and olaparib for germline BRCAs-mutation carriers is paradigmatic of such an advancement in effectiveness and cost-effectiveness of new drugs. We believe that the value of medicines should not be reduced to cost-effectiveness alone but based on patient-centric, multidimensional value framework, including the ESMO Magnitude of Clinical Benefit Scale (MCBS). For neoadjuvant-adjuvant pembrolizumab, and for the adjuvant olaparib, the MCBS scores were A (in a scale of A-C, with A being the highest score), which is consistent with their value for money [65]. Notably, a decrease in cancer recurrences and premature deaths might considerably impact direct and indirect costs of health care, for example, when the drugs are better tolerated and not associated with the risk of severe adverse events and related hospitalizations, are administered orally, require low-intensity of health-care utilization (e.g. no periodic blood tests), and improve significantly the quality of life. Improving patient outcomes in the early setting has potential economic benefits because high-value treatments for eTNBC are administered for a finite interval and portend OS benefits, while therapies in the metastatic setting are commonly administered up to progressions, which means they commonly bring higher costs [64,66]. Henceforth, an economic strive by health-care committees and third-party-payers in the early and thus curative setting seems reasonable for drugs with intrinsic high-value.

In metastatic setting, several new treatment options became available in recent years.

Benefits reported for mTNBC are more heterogeneous. Pembrolizumab and atezolizumab showed to improve the OS of+7 months in the population selected for PD-L1, but a good value for money was not reported in the cost-effectiveness studies. The corresponding MCBS score is 3 (in a scale from 1 to 5). We believe that value frameworks are key to navigate the uncertainties in the effectiveness of new drugs because they can portray the trade-off of efficacy-safety and outline multidimensional, patient-centric evaluations. What is learned from economic evaluations is that the price of these drugs is presently too high to ensure sustainability on the longer term. This is a general problem with ⁶⁷immunotherapy drugs, resulting in struggle for health spending and priority setting. Presently, cost-effectiveness has been estimated with immunotherapy only for limited indications, albeit prices are not set according to the indications, resulting in elevated for both high- and low-value treatments [67]. We reported an economic analysis demonstrating higher economic expediency for pembrolizumab than atezolizumab in the first-line setting from US perspective, but the applicability outside that single model is questionable: multiple strategies exist to enhance sustainability of high-priced cancer medicines, including by optimized, local price negotiations. In general, we endorse context pertinent of economic evaluations, but we are not convinced that a single study on economic modeling, populated with locally relevant variables, should be used to deliberate on the value for money in other settings, or inform the clinical use of the treatments.

For patients harboring deleterious germline BRCA1 and BRCA2 mutations, olaparib and talazoparib provided a better-tolerated regimen with modest PFS gains and no proven cost-effectiveness. Economic evaluations were not better when adjusted for post-trials cross-over⁶⁹ [68]. The lack of cost-effectiveness might be a good argument to support cost rationalization for these drugs, highlighting the potential benefits of oral drugs vs. intravenous compounds, and how it does impact on indirect costs of care. We believe that a comprehensive economic evaluation should capture patient-centric dimensions and cost-effectiveness.

Sacituzumab-govitecan and trastuzumab-deruxtecan for HER2-low TNBC are ADCs that have demonstrated OS benefits and improvements or delayed worsening of health-related quality of life [69]. MCBS scores are 3 and 4, respectively. Cost-effectiveness profile of ADCs is hampered by high-marketed costs and affected by non-trivial toxicities, including interstitial lung disease with T-DXd. Furthermore, economic evaluations in HER2-low TNBC are still characterized by uncertainty of the outcomes, because the pivotal Destiny-Breast04 study had no specific endpoint for TNBC, and the report for these patients is formally descriptive. It is unclear which ADC to prioritize in mTNBC and how to interpret the economic evaluations. Such an uncertainty is not uncommon in health technology assessments, and represents a major determinant of discordance in the outputs of the decisions on reimbursements across different decision-makers [70]. Furthermore, the question of the clinical efficacy of ADC sequencing is further challenged by the lack of data: economic models cannot capture such uncertainty because data on ADC sequencing are scarce, and the benefit of ADC post-ADC is based on assumptions or limited real-world evidence – leading to bias that can affect the reliability of the overall economic exercise [70].

Amidst different economic outputs retrieved from our review, in this era of uncertainties on the efficacy-safety of cancer medicines, and of the fast advent of new paradigms for TNBC treatment, there is no doubt that price-setting will affect the likelihood of access to innovative medicines. Outcome-based pricing for pharmaceutical products is a key process to obtain high-value interventions; real-world data remain the standard instrument to assess efficacy, yet lag time since drug approval could portend an opportunistic window for high price setting, highly unfavorable for health-care systems. In this sense, dynamic outcome-based contracting models, performing a continuous cost-efficacy weighing for the investigational drug in a real-world context, could provide a valuable tool to tackle high drug prices in the setting of efficacy-uncertainty [71].

Nevertheless, we believe that the use of econometric evaluations alone is not sufficient to capture the importance of new drugs for TNBC, albeit a critical complement, and that priority setting should be based on multidimensional, patient-centric, and evidence-based value frameworks such as the ESMO-MCBS. This is in order to prioritize value over cost-effectiveness alone and contextualize the estimates to the patient-relevant dimensions, through innovative approaches to decision-making and reimbursement. We believe that sustainability can only be assured if societal well-being is prospectively improved and by cost-savings.

Article highlights

• Delivering health for all in oncology is a question of cost-effectiveness and should be put in the context of value, budget impact, sustainability, and population health benefits.

• Novel treatment options have been approved for TNBC in early and advanced diseases.

• Novel drugs can lead to economic struggles for health systems due to their high prices.

• Cost-effectiveness of new cancer drugs for TNBC has been reported in the curative setting but not always for metastatic treatments.

• Value-based considerations should drive decision-making, including price-negotiations, based on patient-centric value frameworks like the ESMO-MCBS.

Declaration of interest

G Curigliano received honoraria for speaker, consultancy, or advisory rule from AstraZeneca, Roche, Pfizer, Novartis, Seattle Genetics, Lilly, Ellipses Pharma, Foundation Medicine, Daiichi Sankyo, and Samsung; all are to be intended outside the present work. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

Conceptualization: all authors; Methodology: all authors; Supervision: D Trapani, G Curigliano; Roles/Writing – original draft: all authors; Writing – review & editing: all authors.

Additional information

Funding

This paper was not funded.