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 2018, there were 2.1 million incident cases and 8.6 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 is set to be the first of these therapies approved in early breast cancer, with US and EU regulatory decisions expected towards the end of 2021. 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.
• The PARP inhibitors have become the standard option for 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.
• 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.
• Development of pan-Akt inhibitor ipatasertib was suspended following poor results from the Phase III IPATunity130 trial testing the drug in combination with paclitaxel for the first-line treatment of advanced or metastatic PIK3CA/AKT1/PTEN-altered patients. In the study, ipatasertib failed to improve PFS over placebo in both the HR+/HER2- and triple-negative cohorts. The Phase Ib/III IPATunity150 trial testing ipatasertib in combination with Ibrance and fulvestrant in relapsed HR+ patients is ongoing, but Roche has removed ipatasertib from its breast cancer pipeline and it is not forecast to reach the breast cancer market.
• Several oral SERDs are in late-phase development, being tested against standard hormone therapy across a number of segments. Data are needed from late-phase trials, but improved or comparable outcomes along with oral administration will provide an advantage in select patient populations. Oral SERDs in late-phase development include Roche’s giredestrant, Sanofi’s SAR439859, and AstraZeneca’s AZD9833.
• 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 OS outcomes before considering a regulatory submission. As such, their potential approvals are likely to occur in the late 2020s.
• Key upcoming events include the final OS analysis for eftilagimod alpha in the Phase IIb AIPAC trial, topline results for Trodelvy in the Phase III TROPICS-02 study, first results from elacestrant in the Phase III EMERALD study, as well as a CHMP opinion and EU and US supplementary approval decisions for Verzenio in high-risk, early-stage HR+/HER2- breast cancer patients.
• A relatively high proportion of trials for breast cancer have been in Phase II (44.8%), compared to other indications. The US, Spain, and France have seen the greatest number of breast cancer trials globally. Within Asia, China has the top spot. Clinical trial activity in the breast cancer space is dominated by completed trials. Roche has the highest number of completed clinical trials for breast cancer, with 472 trials.
• The overall likelihood of approval of a Phase I breast cancer asset is 7.9%, and the average probability a drug advances from Phase III is 56.1%. Breast cancer drugs, on average, take 9.7 years from Phase I to approval, compared to 9.6 years in the overall oncology space.