SERENA-2 is a randomized Phase II trial that compares two doses of the novel oral SERD camizestrant with the standard of care fulvestrant. Patients with ER-positive HER2-negative metastatic breast cancer, that were postmenopausal and had progressed to prior endocrine therapy, and were candidates to receive fulvestrant as monotherapy were included in the trial, and randomized to receive camizestrant at 75 milligrams, camizestrant 150 milligrams, camizestrant 300 milligrams or fulvestrant.
ER-positive tumors have different mechanisms of escaping standard therapies like endocrine therapy, and one of them is the emergence of ESR1 mutations. ESR1 mutations lead to an active confirmation of the estrogen receptor, and this makes these tumors resistant to some of the available endocrine therapies. By having more potent agents that could block the receptor and even destroy it, like degrade it, this is the basis for the development of these new drugs that could be active against tumors with ESR1 mutations.
One of the problems with fulvestrant and its administration route is that we cannot achieve high concentrations of the drug in the blood because it's intramuscular. Camizestrant, when given orally, is able to achieve higher concentrations of the drug in the plasma, and then achieve higher inhibitory concentrations for the estrogen receptor. Also, by its pharmacology, it has a more potent activity in inhibiting and also degrading the estrogen receptor. These are all advantages at respect to the standard of care fulvestrant.
We tested three doses of camizestrant initially. The dose of 300 milligrams was discontinued earlier after 20 patients were recruited because of strategic reasons. There were no toxicity concerns. Then we continued to enroll to camizestrant 75 milligram and 150 milligram. The primary endpoint of the trial was to look at PFS and compare each of the camizestrant doses with fulvestrant, and there was no plan to compare the camizestrant doses between 75 and 150.
Camizestrant 75 milligrams reduces the risk of progression or death in about 42% respect to fulvestrant, with a median PFS of 7.2 months compared to 3.7 months with fulvestrant. In respect to the comparison of camizestrant 150 to fulvestrant, the hazard ratio there is 0.67 with a median PFS of 7.7 months for camizestrant 150 and 3.7 months for fulvestrant. Overall survival data right now are not mature. We have a 25% maturity of the overall survival, so these will be presented in a later time point.
The main toxicities related to camizestrant are visual flashes, photopsia is the term we use, bradycardia, and also asthenia and arthralgia. However, it must be noted that the great majority of these toxicities are grade 1. Grade 3 toxicities were very infrequent in the camizestrant arms, and the drug is really very well tolerated as is demonstrated by the extremely low rates of drug discontinuation or dose reduction in the SERENA-2 data sets.
Right now, camizestrant is being tested in two PFO phase three trials, SERENA-4 and SERENA-6. SERENA-4 is testing the combination of camizestrant with palbociclib in comparison with the standard of care aromatase inhibitor plus palbociclib in the first line setting in ER-positive HER2-negative metastatic breast cancer. SERENA-6 is testing the concept of weather switching the endocrine backbone from an aromatase inhibitor to camizestrant in patients that develop an ESR1 mutation can increase the PFS also in the first line setting where these patients are receiving an aromatase inhibitor plus palbociclib.
These are the trials that are being conducted right now, but of course the SERENA-2 results set the stage for camizestrant as a new potential endocrine therapy that will be tested most surely in another context, also.
