The breast cancer drug market

Breast cancer is the most diagnosed cancer worldwide and accounts for the most cancer-related deaths among women. It is a multifactorial disease that can be categorized into three subtypes

according to the hormone receptor (HR) status — oestrogen receptor (ER) and/or progesterone receptor (PR) expression — and human epidermal growth factor receptor 2 (HER2) status. Each

subtype determines the prognosis and choice of treatment. CURRENT TREATMENTS _HER2__+__ BREAST CANCER._ HER2-targeted therapy is the mainstay of treatment. Following the 1998 approval of

trastuzumab, other HER2 therapies have entered the market, including pertuzumab (Perjeta; Roche), trastuzumab emtansine (T-DM1, Kadcyla; Roche), trastuzumab deruxtecan (T-DXd, Enhertu;

Daiichi Sankyo/AstraZeneca), neratinib (Nerlynx; Puma), margetuximab (Margenza; MacroGenics) and tucatinib (Tukysa; Pfizer). Early-stage disease is treated with neoadjuvant trastuzumab plus

chemotherapy (with or without pertuzumab). Patients who do not achieve a pathologic complete response (pCR) receive adjuvant T-DM1 as standard of care. Patients with pCR continue with

adjuvant trastuzumab plus chemotherapy. Pertuzumab may be added for high-risk disease and neratinib as an extended adjuvant treatment. Trastuzumab plus pertuzumab and chemotherapy is the

first-line standard of care for metastatic disease. Since its FDA-accelerated approval in 2019, the next-generation antibody–drug conjugate (ADC) T-DXd has become the second-line standard of

care. It is also being examined as a first-line treatment (in the DESTINY-Breast09 trial) and as (neo)adjuvant treatment for early-stage disease (in the DESTINY-Breast11/05 trial). Another

option for pretreated patients with metastatic disease is tucatinib plus trastuzumab and capecitabine. In August 2023, a phase III trial (HERCLIMB-02) investigating the addition of tucatinib

to T-DM1 met its primary end point of progression-free-survival (PFS) in patients with brain metastasis. _HR__+__/HER2__–__ BREAST CANCER_. Most breast cancers belong to this subtype and

are diagnosed at an early stage. The cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor abemaciclib (Verzenio; Eli Lilly) is approved as adjuvant treatment for node-positive high-risk

patients. Another member of this class, ribociclib (Kisqali; Novartis), significantly improved invasive disease-free survival in patients with intermediate and high-risk disease in the

NATALEE trial; regulatory submissions to the FDA and EMA for adjuvant ribociclib were made at the end of 2023. A phase III trial (KEYNOTE-756) assessing the PD1 inhibitor pembrolizumab

(Keytruda; Merck) as (neo)adjuvant treatment in high-risk patients met one of its dual primary end points of pCR in 2023; assessment of event-free-survival is ongoing. The PARP inhibitor

olaparib (Lynparza; AstraZeneca) is approved for early-stage BRCA1/2-mutated high-risk HER2– disease, but the prevalence of BRCA1/2 mutations in HR+/HER2– disease is low (~3–5%). The CDK4/6

inhibitors palbociclib (Ibrance; Pfizer), ribociclib or abemaciclib, combined with endocrine therapy, are the first-line standard of care for metastatic disease. Three targeted therapies are

approved for endocrine-sensitive patients who progress on first-line treatment: the PI3K inhibitor alpelisib (Piqray; Novartis) combined with the selective ER degrader (SERD) fulvestrant

(Faslodex; AstraZeneca, generics) for PIK3CA-mutant tumours (~40% of cases), the protein kinase B (AKT) inhibitor capivasertib (Truqap; AstraZeneca) plus fulvestrant (approved in November

2023 by the FDA and in June 2024 by the European Commission (EC) for tumours with one or more PIK3CA/AKT1/PTEN-alterations (~50% of cases), and the oral SERD elacestrant (Orserdu; Menarini)

for ESR1-mutated tumours (~30% of cases). Endocrine therapy with or without the mTOR inhibitor everolimus (Afinitor; Novartis, generics) are treatment options regardless of genomic

alterations. Around 50–60% of HR+/HER2– breast cancers are HER2-low (situ hybridization negative (ISH–), immunohistochemistry (IHC) scoring IHC 1+ or IHC 2+). Since 2022, patients in this

subtype are eligible for T-DXd following prior chemotherapy in the metastatic setting. In April 2024, the DESTINY-Breast06 trial investigating T-DXd in chemotherapy-naïve patients with

HER2-low or HER2-ultralow status (ISH-, IHC 0 with faint incomplete membrane staining in ≤10% of tumour cells) met its primary end point with a significant improvement in PFS in HER2-low

patients. The trophoblast cell surface antigen 2 (TROP2)-targeted ADC sacituzumab govitecan (Trodelvy; Gilead) is another option in the third- and later-line metastatic settings, and two

PARP inhibitors — olaparib and talazoparib (Talzenna; Pfizer) — are approved for chemotherapy-treated BRCA1/2-mutated, HER2– metastatic breast cancer. _TRIPLE-NEGATIVE BREAST CANCER_.

Triple-negative breast cancers (TNBC) do not express ER or PR, and are HER2–. Pembrolizumab is approved for high-risk, early-stage disease as (neo)adjuvant treatment. Pembrolizumab plus

chemotherapy is also standard first-line treatment for PDL1-expressing metastatic disease (~40–45% of cases). The PDL1 inhibitor atezolizumab (Tecentriq; Roche) is also approved by the EC in

the same setting. In May 2024, the phase III IMpassion132 trial assessing first-line atezolizumab in PDL1+ patients with early relapse failed to improve OS over chemotherapy. In June 2024,

the CAPItello-290 trial testing capivasertib plus chemotherapy in the first-line setting also failed to improve OS in the entire cohort and in patients with PIK3CA/AKT1/PTEN-mutant tumours.

Sacituzumab govitecan is the standard of care for second- and later-line metastatic TNBC and is being evaluated in three phase III trials (ASCENT-03/04/05) for early-stage and first-line

metastatic disease. Patients with BRCA1/2-mutations (~15% of cases) may receive a PARP inhibitor in the early-stage (olaparib) or in the metastatic setting (olaparib or talazoparib). T-DXd

is an option for those with HER2-low status (~30% of TNBC). EMERGING THERAPIES The breast cancer pipeline is dynamic and spans agents in approved classes as well as drugs with novel

mechanisms of action (Table 1). TABLE 1: SELECT THERAPIES IN THE PHASE III PIPELINE FOR BREAST CANCER Drug Company Mechanism of action Giredestrant Roche SERD Camizestrant AstraZeneca SERD

Imlunestrant Eli Lilly SERD Palazestrant Olema Pharmaceuticals SERD Lasofoxifene Sermonix Pharmaceuticals SERM Vepdegestrant Arvinas/Pfizer ER PROTAC degrader Enobosarm Veru SARM Inavolisib

Roche PI3K inhibitor Gedatolisib Celcuity PI3K / mTOR inhibitor Datopotamab deruxtecan AstraZeneca TROP2-targeted ADC Sacituzumab tirumotecan Merck/Kelun-Biotech TROP2-targeted ADC BNT-323

BioNtech HER2-targeted ADC Atirmociclib Pfizer CDK4 inhibitor Eftiglamod alpha Immutep LAG3 protein, MHC class II agonist Saruparib AstraZeneca PARP inhibitor Zanidatamab Jazz

Pharmaceuticals/BeiGene HER2-targeted bispecific antibody Hormonal therapies feature heavily in the phase III pipeline. Four oral SERDs — giredestrant (Roche), camizestrant (AstraZeneca),

imlunestrant (Eli Lilly), and palazestrant (Olema Pharmaceuticals) — are in trials for early-stage and metastatic HR+/HER2– breast cancer, except for palazestrant, which is only being

investigated in the metastatic setting. Other hormonal therapies in late-phase development include the selective estrogen receptor modulator (SERM) lasofoxifene (Sermonix Pharmaceuticals),

the ER proteolysis-targeting chimera (PROTAC) degrader vepdegestrant (Arvinas/Pfizer), and the selective androgen receptor modulator (SARM) enobosarm (Veru). Two PI3K inhibitors — inavolisib

(Roche) and gedatolisib (Celcuity) are under investigation for metastatic HR+/HER2– breast cancer. A phase III trial (INAVO-120) assessing inavolisib in combination with palbociclib and

fulvestrant for first-line metastatic PIK3CA-mutant HR+/HER2– breast cancer with early adjuvant progression met its primary PFS end point; the agent is under FDA priority review with a

prescription drug user fee act (PDUFA) date of 27 November 2024. A selective next-generation CDK4 inhibitor, atirmociclib (Pfizer), is being tested for metastatic HR+/HER2– patients who have

progressed on a CDK4/6 inhibitor in the FourLight1 trial. The combination of the PARP inhibitor saruparib (AstraZeneca), a CDK4/6 inhibitor and camizestrant in first-line metastatic

HR+/HER2– patients with BRCA1/2 or PALB2 mutations will also be trialled (EvoPAR-BR01). In June 2024, the CDK4/6 inhibitor trilaciclib (Cosela, G1 Therapeutics) failed to improve OS over

chemotherapy as first-line therapy in patients with metastatic TNBC (PRESERVE-2). The TROP2-targeted ADC datopotamab deruxtecan (Daiichi Sankyo/AstraZeneca) is under investigation in five

phase III trials. A trial in chemotherapy-treated metastatic HR+/HER2– breast cancer (TROPION-Breast01) met its primary PFS end point, and the ADC is now under regulatory review in major

markets, with a PDUFA date of 29 January 2025. In TNBC, datopotamab deruxtecan is being assessed in the first-line metastatic setting (TROPION-Breast02/05) and as an early-stage adjuvant

(TROPION-Breast03) or neoadjuvant (TROPION-Breast04) treatment. Another TROP2-targeted ADC — sacituzumab tirumotecan (Merck/Kelun-Biotech) — is being tested for chemotherapy-naïve HR+/HER2–

metastatic breast cancer and in another trial for patients with TNBC without a pCR after neoadjuvant treatment. The HER2-targeted ADC BNT-323 (BioNtech) is under investigation

(DYNASTY-Breast02) in chemotherapy-naïve HR+/HER2-low metastatic breast cancer; a trial (EMPOWHER) has been registered to investigate the HER2-targeted bispecific antibody zanidatamab (Jazz

Pharmaceuticals/BeiGene) in metastatic HER2+ disease. Immune checkpoint inhibitors in the late-phase pipeline include the PDL1 inhibitors durvalumab (Imfinzi, AstraZeneca) and the

first-in-class lymphocyte activating 3 (LAG-3) fusion protein and major histocompatibility complex (MHC) class II agonist, eftiglamod alpha (Immutep). MARKET INDICATORS According to

Clarivate Disease Landscape & Forecast, major-market sales of breast cancer drugs totalled US$28.1 billion in 2023, driven by the strong uptake of CDK4/6 inhibitors ($9.1 billion) and

HER2-targeting agents ($9.6 billion) (Fig. 1). The breast cancer market is forecast to increase 6.7% annually to $50.3 billion in 2032. In 2032, CDK4/6 inhibitors are predicted to have sales

of $14.9 billion, with 57% coming from the early-stage HR+/HER2– segment. As a result of their long treatment durations, substantial sales are expected for adjuvant ribociclib ($4.1

billion) and abemaciclib ($4.4 billion). However, CDK4/6 inhibitor sales will be constrained by generic versions of these agents. T-DXd is expected to be the top-selling drug in 2032 ($9.5

billion), accounting for 54% of sales of HER2-targeting agents; its rapid uptake in approved patient populations and its anticipated label expansions for HER2+ disease will drive market

growth. TROP2-targeted agents are forecast to add around $4.6 billion in sales. Between 2023 and 2032, the market will become increasingly crowded, with novel drugs expected to gain

approval. The entry of premium-priced therapies will boost sales of hormonal agents ($5.5 billion) and AKT/PI3K/mTOR inhibitors ($1.9 billion), but intra-class competition is expected to

constrain uptake of some therapies.