NEWS & ANALYSIS

From the analyst’s Couch The breast drug market

Paul Wilcock and Rachel M. Webster Anthony Nilber Moraes Credit: Stock Photo Paz/Alamy Barros

Breast cancer is the most common cancer in treatment. The first-line​ standard of care 40% of patients) advanced or metastatic women and accounts for the most cancer- for metastatic disease is a cyclin-dependent​ disease, in combination with nanoparti- ​related deaths among women globally. It is a kinase 4 and 6 (CDK4/6) inhibitor — cle (Abraxane, Celgene). The heterogeneous malignancy that is classified (Ibrance, Pfizer), approval of was based on into different subtypes based on the status (Kisqali, ) or (Verzenio/ progression-​free survival data from a the oestrogen receptor (ER) and progesterone Verzenios/Virginio, Eli Lilly) — in combina- phase III trial (IMpassion130); however, in receptor (PR) — collectively known as tion with endocrine therapy. These therapies August 2020, atezolizumab (plus paclitaxel) hormone receptors (HRs) — and the human gained regulatory approval in 2015–2017 and failed to meet progression-free​ survival epidermal growth factor receptor 2 (HER2, have received successive label expansions; as a co-primary​ end point in another trial also known as ERBB2). HR and HER2 status they are also being assessed in late-phase​ (IMpassion131), which treated the same determine drug treatment options. trials as adjuvant treatments for early- popu­lation as in IMpassion130. Other stage disease. The pivotal monarchE trial, phase III trials of atezolizumab are in Current treatments assessing adjuvant abemaciclib, has met its early-stage​ triple-negative​ and HER2-positive​ HER2-positive . Approximately primary end point of invasive disease-free​ disease. 20% of breast are HER2-positive.​ survival. The PD1 inhibitor (Herceptin, Roche) was the In 2019, the FDA approved the PI3K (Keytruda, Merck & Co.) in combination first HER2-​targeting agent to be approved inhibitor (Piqray, Novartis) for with was approved by the (in 1998). Since then, a plethora of HER2- PIK3CA-​mutated (approximately 40% of FDA in November 2020 for the treatment of targeting agents have been approved, includ- patients) advanced or metastatic disease patients with locally recurrent unresectable ing (Perjeta, Roche), trastu- following progression with an endocrine or metastatic triple-negative​ breast cancer zumab emtansine (T-DM1;​ Kadcyla, Roche), therapy. (Afinitor, Novartis) with who express PDL1. Approval was based on (Tykerb/Tyverb, Novartis), is also a treatment option for the KEYNOTE-355 trial. A supplemental (Nerlynx, Puma), HR-​positive/HER2-​negative recurrent disease. Biologics License Application is under FDA (Enhertu, Daiichi Sankyo/AstraZeneca), review for neoadjuvant pembrolizumab in (Tukysa, /Pfizer) and Triple-​negative breast cancer. In 2019, the combination with chemotherapy followed (Margenza, MacroGenics). PDL1 inhibitor atezolizumab (Tecentriq, by adjuvant pembrolizumab for early- Trastuzumab plus chemotherapy with Roche) was granted FDA accelerated stage disease. The user or without pertuzumab is the adjuvant or approval for PDL1-positive​ (approximately fee act (PDUFA) date is 29 March 2021. neoadjuvant standard of care for early- ​stage disease. and neratinib are adjuvant treatment Table 1 | Select therapies in the late-phase​ pipeline for breast cancer options. Pertuzumab plus trastuzumab Product Companies Target Development and chemotherapy is the first-line​ and or MOA status trastuzumab emtansine is the second-line​ Oral paclitaxel + encequidar Athenex Preregistration standard of care for metastatic disease. (Oraxol) However, trastuzumab deruxtecan (approved in 2019), tucatinib plus trastuzumab and Trastuzumab duocarmazine Byondis HER2 Phase III , neratinib plus capecitabine, (Opdivo) Bristol Myers Squibb/Ono PD1 Phase III and margetuximab plus chemotherapy (all approved in 2020) are beginning to erode Ipatasertib Roche//Chugai AKT Phase III trastuzumab emtansine and trastuzumab Capivasertib AstraZeneca AKT Phase III prescriptions for recurrent disease. Balixafortide Polyphor CXCR4 Phase III Trastuzumab deruxetecan is also being tested as a post-neoadjuvant​ treatment, and AbbVie PARP Phase III tucatinib in combination with trastuzumab Elacestrant Radius Health SERD Phase III emtansine is being tested for patients who are trastuzumab-​treated and taxane-treated​ Odonate Therapeutics Taxane Phase III with advanced or metastatic disease. Adagloxad simolenin OBI Pharma Vaccine Phase III

HR-positive/HER2-​ negative​ breast cancer. GDC-0077 Roche/Genentech PI3K Phase II/III Early-stage​ disease is treated with hormonal Lasofoxifene Sermonix Pharmaceuticals SERM Phase II therapy, typically for 5–10 years. Patients AKT, ; CXCR4, CXC chemokine receptor 4; HER2, human epidermal growth factor receptor 2, with intermediate and high-risk​ disease may also known as ERBB2; MOA, mechanism of action; PARP, poly-ADP​ ribose polymerase; SERD, selective also receive chemotherapy prior to hormonal oestrogen receptor degrader; SERM, selective oestrogen receptor modulator.

Nature Reviews | Drug DiSCOvEry volume 20 | May 2021 | 339 NEWS & ANALYSIS

Pembrolizumab is also being assessed in Trastuzumab duocarmazine (Byondis) PARP inhibitors, veliparib is being evaluated early-stage​ ER-positive/HER2-​ negative​ is a HER2-targeting​ ADC that is being with chemotherapy. Two hormonal therapies disease. assessed in pretreated advanced or metastatic are in pivotal trials for pretreated ER-positive/​ Two poly-​ADP ribose polymerase HER2-​positive breast cancer (TULIP trial), HER2-​negative metastatic breast cancer: (PARP) inhibitors are approved for the same population that multiple other elacestrant (Radius Health) and lasofoxifene chemotherapy-pretreated,​ germline HER2-​targeting agents are approved for. The (Sermonix Pharmaceuticals). Other drugs BRCA1/2-mutated,​ HER2-negative​ advanced PD1 inhibitor nivolumab (Opdivo, Bristol in the late-phase​ pipeline include two oral or metastatic breast cancer. The prevalence of Myers Squibb/Ono) is in development , a PI3K inhibitor and a vaccine BRCA1/2 mutations in triple-negative​ (15%) for early-​stage, previously untreated, targeted to Globo H (Table 1). and HR-​positive/HER2-​negative (3–4%) high-risk​ ER-positive/HER-​ negative​ disease breast cancer is low. (Lynparza, (CheckMate 7FL trial), mirroring an Market indicators AstraZeneca) was first to market, followed ongoing phase III trial (KEYNOTE-756) In 2019, the breast cancer market totalled by (Talzenna, Pfizer) (both FDA for pembrolizumab. US$20.2 billion and was dominated by sales approved in 2018); olaparib is also being Two AKT inhibitors are in development of therapies targeting HER2 or CDK4/6 assessed as an adjuvant treatment for high-risk for advanced and metastatic breast cancer. (68% of sales). Despite competition from BRCA1/2-mutated​ HER2-negative​ disease. One of these, ipatasertib (Roche) plus generic and biosimilar agents during our (Trodelvy, chemotherapy is being evaluated with 2019–2029 forecast period, including Immunomedics) is a trophoblast cell surface (IPATunity170) or without (IPATunity130) competitors for the key agents trastuzumab 2 (TROP2)-targeted​ – atezolizumab as a first-line​ treatment for and palbociclib, the breast cancer drug conjugate (ADC). It gained FDA triple-​negative disease. However, primary market is forecast to grow 9% annually accelerated approval in 2020 for third-line​ results from the IPATunity130 trial failed to to $47.7 billion (Fig. 1). The continued and later-line​ metastatic triple-negative​ demonstrate a clinical benefit for ipatasertib uptake and expanded use of CDK4/6 disease based on a single-arm​ phase II trial. in combination with paclitaxel. Ipatasertib inhibitors and entry of 14 premium-priced​ A confirmatory phase III (ASCENT) is also being assessed in combination with agents, including therapies approved in trial is ongoing. It is also in phase III trials palbociclib for HR-positive/HER2-​ negative​ 2019 or 2020 (trastuzumab deruxtecan, for pretreated advanced or metastatic disease (IPATunity150). The other AKT tucatinib, margetuximab, atezolizumab, HR-​positive/HER2-​negative disease inhibitor, capivasertib (AstraZeneca) is being pembrolizumab, alpelisib and sacituzumab (TROPICS-02 trial), and for early-stage​ assessed for triple-negative​ (CAPItello290) govitecan) will fuel this sales growth. HER2-negative​ disease regardless of HR and HR-positive/HER2-​ negative​ By 2029, the CDK4/6 and HER2-targeted​ status (SASCIA trial). (CAPItello291) disease. agents are expected to maintain their share Balixafortide (Polyphor) is a CXCR4 (73%) of breast cancer sales, attributing for Emerging therapies inhibitor. It is being combined with approximately $20 billion and $15 billion, The breast cancer late-phase​ pipeline is (Halaven, Eisai) for pretreated HER2-negative​ respectively. Trastuzumab deruxtecan diverse, spanning approved drug classes recurrent or metastatic breast cancer. is expected to become the top-selling​ and novel mechanisms of action (including Veliparib (AbbVie) is also being developed HER2-​targeted drug owing to its anticipated inhibitors of AKT and CXCR4) in a variety for patients who are HER2-negative,​ but for broad use for HER2-positive,​ HR-positive/​ of treatment settings (Table 1). BRCA1/2-mutated​ tumours; unlike approved HER2-​negative and triple-negative​ cancers and its long treatment duration. The 50 anticipated label expansion of two CDK4/6 47.7 inhibitors (abemaciclib and ribociclib) for 45 42.4 early-stage​ HR-positive/HER2-​ negative​ breast cancer will also drive sales, adding $14 billion 40 in 2029 (69% of drug class sales) in our 35 forecast, with abemaciclib contributing $13 billion (94%) of adjuvant sales. 30 New drug classes are expected to enter the breast cancer market, diversifying treatment 25 Angiogenesis inhibitors options for patients who are triple-negative​ 20.2 CXCR4 inhibitors 20 and HR-positive/HER2-​ negative.​ However, PARP inhibitors sales of some therapies will be constrained TROP2-targeting agents 15 PI3K/AKT/mTOR pathway inhibitors by their biomarker-defined​ populations and

Major-market sales (US$ billions) Major-market Cytotoxic agents approvals in smaller late-line​ populations, 10 PD1/PDL1 inhibitors as well as strong competition from established Hormonal agents and emerging therapies. 5 CDK4/6 inhibitors HER2-targeted agents Paul Wilcock and Rachel M. Webster ✉ 0 2019 2024 2029 Decision Resources Group (part of Clarivate), London, UK. Fig. 1 | Estimated major-market sales of key therapies for breast cancer, by drug class. ✉e-mail:​ [email protected] The figure shows the 2019–2029 forecast for the seven major markets: the USA, France, Germany, https://doi.org/10.1038/d41573-021-00018-6 Italy, Spain, United Kingdom and Japan. AKT, protein kinase B; CXCR4, CXC chemokine receptor 4; CDK4/6, cyclin-dependent​ kinase 4/6; HER2, human epidermal growth factor receptor 2, also Competing interests known as ERBB2; PARP, poly-ADP​ ribose polymerase; TROP2, trophoblast cell surface antigen 2. The authors declare no competing interests.

340 | MAY 2021 | volume 20 www.nature.com/nrd