Early data with oral SERDs indicates encouraging clinical activity, but those Phase I/II trials have been in patients who are heavily pretreated with CDK4/6 inhibitors or hormonal therapies. Credit: Viacheslav Lopatin/Shutterstock.com.

Oral SERDs by AstraZeneca, Sanofi and Radius Health can demonstrate clinical value by being comparable, rather than superior to, AstraZeneca’s Faslodex (fulvestrant) or generic aromatase inhibitors in oestrogen receptor positive (ER+) HER2-negative breast cancer, said experts.

Early data with oral SERDs indicates encouraging clinical activity, but those Phase I/II trials have been in patients who are heavily pretreated with CDK4/6 inhibitors or hormonal therapies, including Faslodex, which is not representative of the Phase II and Phase III trial populations. This dichotomy in patient populations, though standard in early- and late-stage advanced breast cancer drug development, makes it difficult to predict the magnitude of benefit that can be seen in ongoing studies, experts said. Nonetheless, the activity seen in heavily pretreated patients showed a potential for efficacy in ongoing Phase III trials, experts said.

In addition, current data has not indicated any major safety signals, but larger studies are required to identify any tolerability issues. Given preliminary activity and safety data, experts expected these oral SERDs in place of the intramuscular SERD Faslodex. While Phase I amcenestrant data provided further efficacy signals among patients with ESR1 mutations, experts said it was inadequate evidence to be used as a biomarker.

Both AZD9833 (camizestrant) and Sanofi’s SAR439859 (amcenestrant) are now in separate first-line Phase III studies in combination with Pfizer’s CDK4/6 inhibitor Ibrance (palbociclib) versus Ibrance with an aromatase inhibitor. The Phase III SERENA-4 camizestrant trial was started earlier this year, while the amcenestrant trial has a primary completion date in 2024. Moreover, Radius’ oral SERD elacestrant (RAD1901) is being studied in patients who have advanced on at least one endocrine therapy including a CDK4/6 combination, in comparison to Faslodex or an aromatase inhibitor, in a Phase III trial that has a primary completion date in August. Data outlining amcenestrant as a frontline therapy can be expected from a Phase II AMEERA-3 trial in in 1H, as per an analyst report.

Oral SERDs are being closely watched by the market, with the analyst report noting that early amcenestrant/CDK4/6 combination data showed good efficacy and a positive lack of dose reduction due to CV toxicity, unlike competitors. This will be key in the earlier adjuvant setting where it is likely to eventually be investigated.

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Experts expect a class effect among the oral SERDs given their similar mechanisms, but one expert noted that their tolerability profiles could differentiate them once Phase III data with more patients is available. Other SERDs in earlier stages of development include New Orleans, Louisiana-based Zenopharm’s ZB716.

Amcenestrant, camizestrant and elacestrant are expected to yield $506m, $221m and $236m in revenues in 2027, respectively, as per GlobalData Consensus forecasts.

Radius did not respond to a request for comment, while a Sanofi spokesperson did not respond before press time. AstraZeneca is progressing camizestrant with the launch of SERENA-4, and plans to provide updates in the future, said a spokesperson.

Comparable activity to SOC desirable, with encouraging activity seen thus far

Breast cancers progress relatively slowly, and patients tend to be on tamoxifen and Faslodex for many years, said Guangdi Wang, PhD, professor of Chemistry, Xavier University of Louisiana, New Orleans. Therefore, these oral SERDs need to prove equivalent efficacy to a hormonal agent in that setting in larger studies to prove clinical value, he said. Amnescestrant investigator Dr Hannah Linden, physician, Seattle Cancer Care Alliance, Washington, agreed, adding oral SERDs will compete with aromatase inhibitors in combination with CDK4/6 inhibitors received in the first-line (1L) setting. Based on the available data, it is conceivable that these oral SERDs will be effective like aromatase inhibitors and offer an advance in the breast cancer treatment landscape, said Dr Joanne Mortimer, medical oncologist, City of Hope, Duarte, California. Both aromatase inhibitors and Faslodex are approved as 1L and second-line (2L) therapies for HR+ breast cancer patients.

However, it is difficult to gauge whether the observed efficacy will be better than Faslodex because patients have received many different therapies, including Faslodex, said Gregory Thatcher, PhD, professor, Department of Pharmacology & Toxicology, University of Arizona, Tucson. Moreover, individual patient differences and natural history of the disease and timing of recurrence after primary therapy can influence efficacy in these oral SERD trials, said Thatcher and Linden.

Nonetheless, experts agreed the early data indicated the oral SERDs are at least active in a heavily pretreated population. For example, in a Phase I/II amnescestrant study where 74.2% of participants had prior targeted therapy, a clinical benefit rate (CBR) of 35.6% was reported (Campone et al., Journal of Clinical Oncology 38, no. 15_suppl, May 20, 2020; 1070-1070). Similarly, Wang said he found camizestrant potent, but retained some caution in the absence of long-term safety and efficacy data. A CBR of 42.3% was reported among 52 patients in a Phase I camizestrant study, where 82% received prior Faslodex (Hamilton et al., Journal of Clinical Oncology 38, no. 15 suppl, May 20, 2020; 1024-1024). Similarly, elacestrant is associated with a CBR of 42.6% among 57 patients in a Phase I study (Bardia et al., Journal of Clinical Oncology, epub: 29 January, 2021). Typically, once ER+ Her2-negative patients progress after a couple of lines of endocrine therapy, the response rates drop to less than 10% or responses are not expected, said Dr Robert Wesolowski, medical oncologist, Ohio State University, Columbus.

Even though it is difficult to predict potential efficacy, there may be a class effect among the different oral SERDs, said Linden. However, Thatcher noted that elacestrant has “modulator”-like activity, while Faslodex is a pure antioestrogen drug, with amnescestrant and camizestrant having middling activity between the two.

No safety concerns yet in smaller studies

When healthier and younger women get breast cancer, the balance between treatment options and the effect on quality of life (QoL) becomes more important, said Thatcher. Tolerability will be a big question, and QoL data will be helpful in that regard, said Linden. In the amnescestrant trial, the most common adverse events included hot flush in 16.1% patients and constipation and arthralgia each in 9.7% of patients. The most common side effects seen with camizestrant included visual disturbances, bradycardia/sinus bradycardia and nausea. Adverse events like fatigue, nausea and vomiting have been observed with oral SERDs, but it is difficult to tell in early-phase studies whether they relate to the drug or to patients having a high burden of metastatic disease, said Wesolowski. Of note, there have been no dose-limiting toxicities observed for these therapies in the smaller studies, said Thatcher. However, both Thatcher and Linden added that the safety still needs to be investigated in larger Phase III trials. Wang agreed, adding that any debilitating vision or cardiotoxicities can only be observed in larger studies.

Nonetheless, oral SERDs offer an advantage since Faslodex is viscous and its intramuscular administration can take time and can be painful to administer, said Wesolowski. Once there is more than one option available, the choice of oral SERD could depend on precision medicine techniques such as age and ER expression to identify the patients most likely to respond, said Thatcher. ESR1 pathways are upregulated in metastatic disease, which leads to resistance to endocrine therapy with aromatase inhibitors, explained Linden. However, the oral SERDs are active in patients with ESR1 mutations and in those without those mutations, she added.

Manasi Vaidya is an Associate Editor for Pharmaceutical Technology parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.