Next Generation SERDs Progress In Breast Cancer; Standing Out In The Crowd Won't Be Easy
Executive Summary
The class is poised to be a competitive one with Sanofi, AstraZeneca, Roche and Zentalis among the contenders developing new selective estrogen receptor degraders for HER2-negative breast cancer.
Several selective estrogen receptor degraders (SERDs) are progressing into mid-stage development as potential options for human epidermal growth factor receptor 2 (HER2)-negative, hormone receptor (HR)-positive breast cancer. Early clinical data for several of the next generation hormonal therapies were presented at the American Society of Clinical Oncology virtual meeting 29-31 May, including drugs from Sanofi, AstraZeneca PLC and Roche.
The maturing data put a renewed spotlight on the class of drugs. Another drug maker, Zentalis Pharmaceuticals, which had an initial public offering in April after an all virtual roadshow, has a lead drug that is a SERD in development, but did not report data at ASCO. Zentalis' ZN-c5 is in Phase I/II testing with data expected in the second half of 2020. (Also see "Post-IPO Zentalis Plows New Ground With China Oncology Venture" - Scrip, 21 May, 2020.) The class is poised to be competitive and it’s too early to understand if any one drug will have an edge over its rivals, but it is clear that safety could be a big factor within the class.
The mechanism is getting attention in part because the new SERDs in development are oral drugs, which would be a big benefit over the only SERD on the market, fulvestrant (AstraZeneca's Faslodex and generics), which is administered via intramuscular injection. Fulvestrant is an older drug that has been on the market since 2003, but it is frequently used in combination with a newer class of drugs, the CDK4/6 inhibitors like Pfizer Inc.'s Ibrance (palbociclib) to treat HER2-negative, ER-positive advanced or metastatic breast cancer.
Many breast cancers have estrogen receptors and the tumors are stimulated by estrogen. Older hormone therapies work to dial down the activity of the estrogen receptors but SERDs aim to block the pathway entirely. There is room for improved efficacy on this front over fulvestrant as well.
To be commercially successful, the next generation SERDs will need to have an efficacy advantage over existing hormone therapies, including aromatase inhibitors, which are commonly used in breast cancer and in combination with CDK4/6 inhibitors, and they will need to be safe.
Sanofi Is An Early Leader With Good Safety Profile
Coming out of ASCO, Sanofi appears to have a small edge over competitors with SAR439859 because of a favorable tolerability profile, particularly around cardiac safety.
At ASCO, Sanofi presented data from AMEERA-1, a monotherapy dose-escalation trial in heavily pretreated metastatic breast cancer patients, with more than half having three lines of prior therapy. Results showed a 36% clinical benefit rate and a solid tolerability profile. In a subpopulation of patients who have not received prior fulvestrant or a CDK4/6 inhibitor, the clinical benefit rate was higher, 64%. An expansion phase testing '859 in combination with Ibrance is continuing.
The safety profile is particularly important as some rival SERDs in development have shown a worrying safety signal of bradycardia. In AMEERA-1, there were no adverse events that were Grade 3 or greater. The clean safety profile with '859 could help Sanofi over rivals when it comes to enrolling patients in clinical trials, and the company believes it could have a one-year head start to the market over the competition.
The molecule was highlighted by Sanofi as a future growth driver for the company and a key part of its oncology revival in December during CEO Paul Hudson's first capital markets day, with management pointing to the drug's "exquisite" safety profile as an opportunity for it to become the standard of care.
During a virtual presentation on 2 June highlighting data presented at ASCO, global oncology development head Peter Adamson said, "We believe '859 has the potential to be a best-in-class endocrine backbone therapy for patients with hormone receptor-positive breast cancer."
The company is focusing initially on developing it as a single agent in second-line metastatic breast cancer as part of a fast-to-market approach. Then, Sanofi plans to focus on expanding development to combinations with CDK4/6 inhibitors in the metastatic setting, and third, into the earlier treatment setting.
"Our goal is to have '859 become the endocrine backbone across all lines, all the way into early breast cancer," Adamson said. The company has targeted a regulatory filing date for '859 in the second half of 2021.
AstraZeneca And Roche Encouraged, Despite Safety Issues
AstraZeneca – which has experience in the area with Faslodex and is rebuilding a breast cancer franchise with the launch of Enhertu (fam-trastuzumab deruxtecan) for HER2-negative breast cancer – is developing the next-generation SERD AZD9833.
At ASCO, AstraZeneca reported data from SERENA-1, an ongoing Phase I open-label study in pre- and post-menopausal women with ER+, HER2- advanced breast cancer who had received multiple lines of prior therapy. In the first 60 patients treated, the clinical benefit rate (CBR) was 42.3%. However, there were treatment-related adverse events including bradycardia (45%) and visual disturbances (53%).
"What we have seen is encouraging clinical activity at multiple dose levels and a dose-dependent safety profile," VP-oncology R&D José Baselga said during a 1 June virtual presentation of ASCO data. Of the cases of bradycardia, he said it appears to be a class effect and that the number of interruptions due to bradycardia or other side effects in the trial appear to be low. He said the visual disturbances were minimal disturbances that occur when there's a change in lighting conditions and did not interfere with physical activity.
"Based on this data, we are going to be launching a number of Phase III clinical trials in ER-positive breast cancer," Baselga said.
Roche, meanwhile, presented data from a Phase Ib study testing the safety of GDC-9545 alone or in combination with palbociclib in metastatic ER-positive, HER2-negative breast cancer with two or less prior therapies and no prior CDK4/6 treatment. The trial enrolled 85 patients in two cohorts. There were three cases of bradycardia in Cohort A, in which patients were treated with GDC-9545 plus an LHRH agonist, and there were 25 cases of bradycardia on Cohort B. No patients in either cohort discontinued treatment due to adverse events. The clinical benefit rate was 55% in Cohort A and 81% in Cohort B.
Further evaluation is ongoing in an expansion cohort testing GDC-9545 at 30mg, given a clinical benefit rate of 50% and no cases of bradycardia seen at that dose.
Analysts were cautiously optimistic about the emerging data on the SERD class, but said more data would be needed.
"It's hard to draw any conclusions from a comparison of these early data but broadly it looks like Sanofi's SERD may have a favorable tolerability profile," Jefferies analyst Peter Welford said in a 31 May report. "The commercial opportunity for oral SERDs depends on them having an advantage of aromatase inhibitors (AIs) and ultimately whether they can be used in the adjuvant setting."
Adjuvant therapy is given after primary surgery and the long duration of use could mean a big potential commercial opportunity.
In a disappointment for the field, Pfizer reported during ASCO that a big study, PALLAS, testing Ibrance in the adjuvant setting was unlikely to meet the primary endpoint of invasive disease-free survival. (Also see "Pfizer’s Hopes For Ibrance In Adjuvant Breast Cancer Fall With PALLAS" - Scrip, 1 Jun, 2020.)
The study compared Ibrance plus standard adjuvant endocrine therapy to standard endocrine therapy alone in patients with HR-positive, HER2-negative breast cancer. With the failure of PALLAS, however, it may be possible for an oral SERD to show a benefit over aromatase inhibitors in the adjuvant setting.