OP-1250 and palbociclib showed “enhanced suppression of tumor growth” in preclinical mouse model studies, according to expert who presented his findings in a poster at the San Antonio Breast Cancer Symposium 2022.
Pharmacy Times interviewed Sean Bohen, MD, PhD, CEO, Olema Oncology, who discussed data from a preclinical, phase 1b/2 trial that supports the combination of complete estrogen receptor antagonist, OP-1250, and CDK4/6 inhibitors for women with (ER)-positive HER2 negative breast cancer.
PT Staff: How do OP-1250 and CDK4/6 inhibitors work together to enhance tumor suppression and inhibition of cell cycle-related gene expression?
Sean Bohen, MD, PhD: OP-1250 and cyclin-dependent kinase (CDK)4/6 inhibitors are acting on 2 different mechanisms that cancer cells use to promote their abnormal growth and proliferation. In the case of OP-1250, the molecule acts through the estrogen receptor. The estrogen receptor in breast cancer cells is used by the cancer to inappropriately go through the cell cycle and grow and proliferate by inducing cell cycle proliferation genes.
OP-1250 completely antagonizes the estrogen receptor, so it turns the estrogen receptor off completely— both in the cases of wild type receptors and when receptors contain an activating mutation (which allows the receptor to activate transcription even if estrogen isn't present.) So OP-1250 is a complete estrogen receptor antagonist (CERAN) and a selective estrogen receptor degrader (SERD).
CDK4/6 inhibitors also slow down and inhibit progression through the cell cycle on breast cancer cells. They do it in a different way. They inhibit 2 different cyclin dependent kinases, CDK4, and CDK6. And when you combine the 2 mechanisms, ER antagonism and CDK4/6 inhibition, you get both enhanced suppression of tumor growth. And, in this study, shrinkage of the tumors. And also you see that the genes that are expressed as you go through the cell cycle to progress to growing, more tumor cells are suppressed by this combination.
PT Staff: What were the endpoints of this preclinical experiment, and how were the outcomes measured?
Sean Bohen, MD, PhD: There are 2 endpoints that are that are captured in this particular experiment. One is to look at xenograft tumors. So these are these are tumors derived from breast cancer cell lines or patient derived xenografts actually taken from breast cancer patient cells, and they're implanted into mice. The tumors are allowed to grow and establish themselves, then the treatment is started with either OP-1250 at different doses, CDK4/6 inhibitors palbociclib, or ribociclib, at different doses—and then a combination of OP-1250 and 1 or the other CDK4/6 inhibitors.
And what is measured is the size of the tumor. So, in the case of no treatment, or suboptimal treatment, the tumors continue to grow. In the case of optimal treatment with OP-1250, a CDK4/6 inhibitor or even more so in the combination, you see shrinkage or regression of the tumors. The other thing that was shown here was gene expression of cell cycle-related genes, genes that change their expression level dependent on where the cell is in progressing through the cell cycle. And what we saw there was that there was a decrease in the cell cycle related genes, both with treatment with OP-1250, and with treatment with CDK4/6 inhibitors, but then even more so with the combination.
PT Staff:In this preclinical experiment, what did the results show regarding the safety and efficacy of each combination?
Sean Bohen, MD, PhD: So with regard to the efficacy seen in these preclinical experiments, we saw robust tumor shrinkage with relatively high doses of OPI trophy and also of either CDK4/6 inhibitor palbociclib, or ribociclib. What was interesting was that you saw even more robust tumor shrinkage when you combined the 2 agents—either OP-1250 and palbociclib, or OP-1250 and ribociclib at even lower doses.
So more than additive activity. This was seen in both the xenograft models that we saw, and in the result. And this did result in longer survival of the mice that were carrying these patient-derived xenograft tumors.
In addition, what was measured is the gene expression related to cell cycle progression. And again, that's a place where there was some activity in suppressing those cell cycle-related genes with either OP-1250 or the CDK4/6 inhibitor— but it was even greater. It was super additive in the gene transcriptional repression was even greater, it was super additive, when you combined either of the CDK4/6 inhibitors with OP-1250. In terms of safety, this was really a preclinical study this is a mouse tumor model experiment, so it is not really a safety study. However, the enhanced survival with the combination treatment shows that the mice carrying the tumors did do better with a combination than with either single agent alone.
PT Staff: What are the implications of these results and subsequent next steps?
Sean Bohen, MD, PhD: Well, the implications are really to support the ongoing clinical studies in patients with (ER)-positive or HER2 negative breast cancer of OP-1250 combined with palbociclib. The clinical trial is beginning to show the combination ability of OP-1250 and palbociclib. It is also being presented in a poster, a phase 1a clinical trial poster, at the San Antonio Breast Cancer Symposium. We also have an ongoing trial of OP-1250 and ribociclib—that trial is not being presented at the symposium but is currently enrolling what these patient xengraft studies give us—a biological basis for the potential superiority of the combination of OP-1250 and a CDK4/6 inhibitor over either agent alone in the treatment of (ER)-positive HER2 negative breast cancer.