Disease Analysis: HR+/HER2- Breast Cancer

Overview

Hormone receptor-positive (HR+) is the most common breast cancer subtype, with approximately 70% of breast cancers presenting with overexpression of estrogen receptors, progesterone receptors, or both. Overexpression of the hormone receptors allows estrogen and progesterone to drive tumor growth and proliferation. Therefore, endocrine therapy remains the standard treatment for advanced patients with HR+/human epidermal growth factor receptor 2-negative (HER2-) breast cancer.

Latest key takeaways

• Datamonitor Healthcare estimates that in 2021, there were 2.2 million incident cases and 8.8 million five-year prevalent cases of breast cancer worldwide. By 2027, incident and prevalent cases of breast cancer are expected to increase to 2.3 million and 9.3 million cases, respectively.
• CDK4/6 inhibitors remain the standard treatment for advanced and metastatic HR+/HER2- patients. Datamonitor Healthcare expects their uptake to increase significantly over the forecast period as Verzenio and Kisqali are projected to receive strategic label expansions into the adjuvant treatment setting for early-stage HR+/HER2- breast cancer patients. Verzenio was the first of these therapies to be approved in early breast cancer in the US (in October 2021), with EU regulatory decisions expected during 2022. Submissions were based on positive results from the Phase III monarchE trial. Ibrance is not forecasted to receive a similar approval after the failure of the PALLAS and PENELOPE-B trials.
• PARP inhibitors have become the standard option for germline BRCA1/2-mutated (gBRCAm) breast cancer patients. Despite their efficacy in this population, their overall commercial potential will remain limited in the near term by their positioning in this niche segment. Expansion into the adjuvant setting for earlier-stage disease will improve their outlook, beginning with Lynparza, which improved the risk of invasive breast cancer recurrence, second cancer, or death by 42% over placebo in the Phase III OlympiA trial, resulting in approval for this patient segmentation.
• Fulvestrant remains a key therapy across patient segments. Guideline recommendations for use at first line and subsequent lines of therapy, an indication for use in combination with the CDK4/6 inhibitors, as well as expansion as part of a combination with Piqray highlight its broad utility. However, generic competition will continue to erode branded Faslodex’s market share.
• Piqray is the first PI3K inhibitor approved for use in breast cancer. The overall potential of Piqray will be somewhat limited by its side-effect profile that includes high rates of neutropenia, nausea, hyperglycemia, and diarrhea. It also faces potential intra-class competition from late-phase PI3K/Akt/mTOR pathway inhibitors ipatasertib, capivasertib, and inavolisib.
• Afinitor remains a standard option for patients who progress on prior endocrine therapy, and is typically used post-CDK4/6 inhibitor treatment. However, generic versions of the drug will continue to take market share over the forecast period.
• Generic and biosimilar versions of key branded therapies will slow growth of the HR+/HER2- breast cancer market. The largest impact will come from palbociclib generics, although their launch is now delayed until at least 2027 following the extension of Ibrance’s key ‘739 patent.
• Several oral SERDs are in late-phase development, being tested against standard hormone therapy across a number of segments, although the failures of amcenestrant and giredestrant to reach their primary endpoints in recent trials may reflect badly on the drug class. Data are needed from late-phase trials, but improved or comparable outcomes along with oral administration would provide an advantage in select patient populations. Oral SERDs in late-phase development include Roche’s giredestrant, Sanofi’s amcenestrant, AstraZeneca’s camizestrant, Menarini Group’s elacestrant, and Eli Lilly’s imlunestrant.
• Checkpoint inhibitors are now being trialed in the early-stage segment of HR+/HER2- breast cancer. The PD-1 inhibitors Keytruda and Opdivo are being studied as periadjuvant therapies for high-risk, early-stage HR+/HER2- breast cancer patients in the Phase III KEYNOTE-756 and CheckMate 7FL studies, respectively. Data are lacking from these trials, and it is likely that regulatory agencies will wait for event-free survival or even overall survival outcomes before considering a regulatory submission. As such, their potential approvals are likely to occur in the late 2020s.
• The antibody-drug conjugate Enhertu, being investigated in the Phase III DESTINY-Breast04 trial, has demonstrated efficacy in HER2-low patients, positioning it to become a potential new standard of care in the later-line metastatic setting. Numerical data are yet to be released, but this is an area of high unmet need and positive results could result in significant uptake.
• The HR+/HER2- pipeline is very active, with agents datopotamab deruxtecan and enobosarm currently being investigated in Phase III clinical trials.
• The overall likelihood of approval of a Phase I breast cancer asset is 7.7%, and the average probability a drug advances from Phase III is 55.7%. Breast cancer drugs, on average, take 10.0 years from Phase I to approval, compared to 9.7 years in the overall oncology space.
• Key upcoming events include updated results for Trodelvy in the Phase III TROPICS-02 study, and an EU supplementary approval decision for Verzenio in high-risk, early-stage HR+/HER2- breast cancer patients.