NEW YORK – By engineering a more comprehensive blockade of the estrogen receptor, Olema Oncology believes it can overcome the weaknesses of next-generation selective estrogen receptor degraders (SERDs) in ER-positive, HER2-negative breast cancer patients.
Olema is advancing its lead compound OP-1250 in a Phase II single-agent trial and in two Phase Ib combination trials in advanced breast cancer, one with Pfizer's Ibrance (palbociclib) and a newly initiated trial in collaboration with Novartis, combining OP-1250 with the CDK4/6 inhibitor Kisqali (ribociclib) or the PI3 kinase inhibitor Piqray (alpelisib). The OP-1250-Piqray combination is under development in patients whose tumors bear a PI3 kinase activating mutation.
OP-1250 is both a SERD and an estrogen receptor antagonist. Because of the totality of the estrogen receptor blockade, Olema refers to it as a complete estrogen receptor antagonist, or CERAN. With these combined mechanism, plus growing evidence that SERDs can overcome resistance caused by mutations in ESR1, Olema's President and CEO Sean Bohen believes that OP-1250's potential in breast cancer could be comparable to the success of AstraZeneca's Tagrisso (osimertinib) in non-small cell lung cancer.
Tagrisso, which is approved for the treatment of EGFR-mutated NSCLC, suppresses EGFR T790M, the most common mutation associated with resistance to first-generation tyrosine kinase inhibitors. Bohen, who was previously chief medical officer and VP of global medicines development at AstraZeneca, and oversaw the development of the EGFR inhibitor, said that similarly, "OP-1250 has the ability to suppress the most common resistance mutation [in ER-positive breast cancer]."
Comparing OP-1250 to Menarini's SERD elacestrant, which showed an improvement over fulvestrant with an aromatase inhibitor in the second-line setting in the Phase III EMERALD trial, Bohen is betting that OP-1250, being a more complete blocker of the estrogen receptor, could outperform elacestrant in the second- and third-line setting both in wild type and ESR1-mutant populations. And the US Food and Drug Administration acknowledged that potential in July by granting fast track designation to OP-1250 for ER-positive, HER2-negative breast cancer in the second-line setting.
Olema's expectations for OP-1250 are based on preclinical data showing that the drug shrinks ER-positive breast tumors in mouse models, including in wild-type tumors and intracranial tumors expressing the ESR1 Y537S mutation. The drug also prevented tumor spread in a mouse model of ESR1-mutated ER-positive breast cancer. "We are able to shrink tumors in models where the best response from fulvestrant is only to slow tumor growth," said Bohen. The firm also has some early clinical results showing tolerability and anti-tumor activity.
Looking at the totality of the data generated on SERDs and selective estrogen receptor modulators (SERMs) in ER-positive breast cancer, it appears that the efficacy of these drug classes is closely tied to how well the agents inhibit the estrogen receptor. In breast cancers that express estrogen receptor-α (ERα), the normal signaling processes associated with functions like female breast development are hijacked to promote the growth of cancer. Tamoxifen, approved by the FDA in 1977, was the first SERM and remains the therapy of choice for premenopausal women with ER-positive breast cancer. Tamoxifen binds ERα, inhibiting proliferation of cancer cells.
However, 30 percent to 50 percent of ER-positive tumors eventually become resistant to treatment with tamoxifen or an aromatase inhibitor. Fulvestrant, the first SERD, has become a standard treatment for advanced HR-positive, HER2-negative breast cancer. Rather than merely binding and inhibiting ERα, fulvestrant induces degradation of the receptor, but isn't without limitations. Most significantly, it must be given by injection, which limits the amount of drug the body can take up, leading to incomplete blockade of the estrogen receptor.
A new generation of SERDs and SERMs have entered clinical development in the hopes of overcoming the limitations of fulvestrant and tamoxifen. However, these novel compounds, other than elacestrant, have mostly not improved on those older treatments, except in the subset of patients whose tumors bear the ESR1 resistance mutation.
Last month, Sanofi discontinued development of its SERD, amcenestrant, after an interim analysis of its Phase III AMEERA-5 trial showed that the drug failed to meet a prespecified endpoint. Similarly, Roche's SERD giredestrant failed to meet its endpoint of improved progression-free survival when compared to physician's choice of endocrine monotherapy in the Phase II acelERA trial.
"The problem with selective estrogen receptor degraders is that they don't degrade adequately to suppress the estrogen receptor signal," Bohen explained. "In the most ideal cell culture situation, the degradation leaves about 20 percent of the estrogen receptor still present." That's enough remaining activity, he said, to continue fueling transcription and synthesis of proteins and enable ER-positive cancer cells to grow and proliferate.
OP-1250's degradation activity is as strong as any of the next-generation SERDs, according to Bohen. But with the additional CERAN function of the molecule, it has the ability to occupy the remnant of the receptor and turn off all transcriptional activation. That means not only does OP-1250 inactivate wild-type estrogen receptors by competing with its natural ligand, 17β-estradiol, it also deactivates ESR1-mutated estrogen receptors, which no longer depend on 17β-estradiol binding for their activity.
Previously known as CombiThera, the San Francisco-based company was renamed Olema and rebranded in 2020 as a company developing treatments for women's cancers. CombiThera had been focused on developing off-patent drugs into novel combination treatments. Bohen called that approach, which has been tried multiple times by multiple companies, misguided, primarily because intellectual property rights are no longer available and fixed-dose combinations are not flexible enough to meet patient needs.
The company then turned to developing treatments for endocrine-driven cancers for several years before discovering OP-1250. Bohen said that although Olema did not test any compounds in the clinic prior to OP-1250, the firm applied the lessons from past mistakes when developing the therapeutic profile of the drug.
The OP-1250 development team started with a very specific wish list of features they wanted the drug to have based on observations of pharmaceutical successes and failures in treating estrogen-driven breast cancers. "We wanted a potent, complete antagonist. We felt that degradation was a red herring because it's so incomplete," said Bohen.
As well, Olema prioritized compounds that were bioavailable with daily oral dosing and a "tamoxifen-like" half-life in the body. Other requirements included a molecule that is not inactivated by covalent modifications in the body and does not metabolize partner compounds, such as CDK4/6 inhibitors. Bohen pointed out that amcenestrant decreases exposure of Ibrance when given together.
OP-1250 checks all of these wish list items and has a bonus feature — it crosses the blood-brain barrier, opening up treatment avenues for patients with central nervous system metastases. Bohen said that it is "unique to have a company assessing the activity of [a drug] so early in development in the CNS metastasis setting."
Two years ago, $54 million in Series B financing helped Olema launch OP-1250 into Phase I/II clinical development. The company has now completed the Phase I dose escalation stage of this study and entered the Phase II expansion stage. Having established a recommended Phase II dose of 120 mg OP-1250 once daily, Olema is recruiting 50 patients with measurable ER-positive, HER2-negative breast cancer, 15 patients with non-measurable disease, and 15 patients with CNS involvement. In its Phase Ib trial of OP-1250 combined with Ibrance, Olema has also gone through the dose escalation process and is studying the 120 mg dose in an expansion phase, according to Bohen.
Olema expects to present data from the Phase II monotherapy study of OP-1250 and from the Ibrance combination study at a medical meeting in the fourth quarter of 2022.
Finally, Olema is planning its first pivotal trial of single-agent OP-1250 in second- and third-line ER-positive, HER2-negative breast cancer that has progressed following one or more lines of endocrine therapy to begin in the middle of 2023. The trial will compare OP-1250 to a standard-of-care therapy, which typically is fulvestrant, but could also be an aromatase inhibitor or potentially tamoxifen.