Sean P. Bohen, MD, PhD, Olema Oncology President and CEO

While biopharma giants showed mixed results in 2022 trying to treat breast cancer with selective ER degraders (SERDs), a much smaller drug developer is preparing to test a two-prong approach to beating the disease in a pivotal trial.

Olema Oncology plans in mid-year to launch a Phase III study for its lead candidate OP-1250 that will assess the oral small molecule as a monotherapy for second- and third-line treatment for estrogen receptor-positive (ER+)/ human epidermal growth factor receptor 2 (HER2)-negative breast cancer.

OP-1250 is both a SERD and a complete ER antagonist (CERAN). As a result, Olema reasons, OP-1250 could emerge as a backbone endocrine therapy of choice for the roughly 80% of breast cancer cases categorized as ER+ by delivering the best of both modalities: By fully blocking the estrogen receptor and the signaling pathway as a CERAN, and by generating increased durability and deeper anti-tumor activity as a SERD.

“It completely suppresses the growth and proliferation signal mediated by the estrogen receptor,” Olema President and CEO Sean P. Bohen, MD, PhD, told GEN Edge. “In addition, it has very favorable pharmacokinetics: It has about an eight-day half-life with oral daily dosing. Its tolerability is favorable. And as we’re learning now, its combinability is favorable as well.”

Another interesting property of OP-1250, Bohen said, is its ability to cross the blood-brain barrier.

“We’re trying to think about ways that we might exploit that to use an endocrine therapy for the treatment of CNS metastases associated with breast cancer,” Bohen said. “The net effect of those various pharmacological properties, in addition to being a complete estrogen receptor antagonist, is that we are able to get a very robust drug level in the patient, and that allows us to occupy and turn off the receptor all of the time, which is the objective of therapy.”

At the recent San Antonio Breast Cancer Symposium, Olema presented data from a Phase Ib dose escalation study showing early signs of clinical activity and a positive safety/ tolerability for the combination of OP-1250 and palbociclib, an inhibitor of cyclin-dependent kinase 4 and 6 (CDK 4/6) that is marketed by Pfizer as Ibrance®.

OP-1250 plus palbociclib showed stable disease (SD) in the three patients at the highest of four doses studied (120 mg) at between four and 10 weeks of follow-up, as well as  two of the three patients given the 90 mg dose at between 12 and 16 weeks of follow-up. Each of the patients in the 120 mg dose were ESR1 wild-type, and all had previously been treated with a CDK4/6i and an AI or fulvestrant (a SERD marketed by AstraZeneca as Faslodex®).

Faslodex’s U.S. patents expired in 2021. Growing generic competition has shrunk sales of the drug to $259 million in Q1-Q3 2022, down 21% from a year earlier (Faslodex generated $431 million in 2021). The resulting scramble has compelled Olema and other companies to pursue new treatments for ER+/HER2- breast cancer.

Early signs of efficacy

“These are encouraging early signs of efficacy, and the next step is to watch for duration and depth of response, expecting some stable disease to deepen into partial responses,” Bill Maughan, PhD, Equity Research Senior Analyst–Biotechnology with Canaccord Genuity, wrote in a December 8 research note.

He noted that ongoing stable disease was seen among patients with differing treatment histories, as well as ESR1 mutational status: “It is encouraging that one or more ongoing SD was observed in each of the six patient groupings based on prior lines of treatment, indicating that OP-1250 + palbociclib may have broad commercial potential.”

Olema continues to recruit patients for the dose expansion study at the recommended Phase II dose of 120 mg OP-1250 + 125 mg palbociclib. Data from that study is expected to be presented later this year.

When it does, Maughan wrote, he believes that the OP-1250/palbociclib combination data could mature with more encouraging results beyond the five of eight SD patients reported with less than 16 weeks of follow-up, based on OP-1250’s cytostatic mechanism of action and the observed deepening of responses from SD to partial recovery occurring between about 6 to 16 weeks in Olema’s Phase I/II monotherapy trial of OP-1250.

“Overall, we continue to think that OP-1250’s profile is highly competitive in a field that has been winnowed down by a string of competitive failures, offset by some late-line successes that have validated the potential for an oral SERD in late-line monotherapy.”

Two of those failures came from biopharma giants seeking to develop SERDs in breast cancer. In August 2022, Sanofi scrapped its global clinical development program of amcenestrant after a negative interim analysis of the Phase III AMEERA-5 trial (NCT04478266), assessing the SERD plus palbociclib compared with letrozole plus palbociclib in ER+/HER2- advanced breast cancer.

Five months earlier, in March 2022, amcenestrant failed the Phase II AMEERA-3 trial (NCT04059484) by missing the study’s primary endpoint of improving progression-free survival compared to endocrine treatment of physician’s choice in patients with locally advanced or metastatic ER+/HER2- breast cancer who progressed on or after hormonal therapies.

Also failing a clinical study was Roche’s giredestrant, which in July missed its primary endpoint in the Phase II acelERA trial (NCT04576455) by failing to show statistically significant progression-free survival (PFS) in people with ER+/HER2- locally advanced or metastatic breast cancer who had received one or two prior lines of systemic therapy, compared with physician’s choice of endocrine monotherapy (PCET).

However, two months later, Roche presented data at the 2022 European Society for Medical Oncology (ESMO) Congress that the investigator-assessed median PFS among the study’s 151 giredestrant patients was 5.6 months, compared with 5.4 months among the 152 PCET patients. The 6-month PFS rates were 46.8% in the giredestrant arm and 39.6% in the PCET arm. Roche also noted over the summer that giredestrant showed improved efficacy and good safety results in an earlier Phase II trial (coopERA, NCT04436744).

Giredestrant remains in Phase III development in three indications that are on track for regulatory filings in 2025 or later: First-line ER+/HER2- metastatic breast cancer (mBC); first-line ER+/HER2+ breast cancer; and adjuvant ER+ breast cancer. Giredestrant is also in Phase I development for solid tumors.

Acing phase III

By contrast, the Menarini Group and its Stemline Therapeutics subsidiary reported strong positive Phase III data at SABCS for their oral SERD elacestrant.

Elacestrant aced the 478-patient registrational EMERALD trial (NCT03778931) by showing a median PFS of 3.8 months in 150 patients treated with a CDK 4/6 inhibitor for 12 months or more compared with 1.9 months for standard of care (fulvestrant, anastrozole, letrozole, or exemestane) in 160 CDK4/6i patients—a 39% reduction in the risk of progression or death. Among the 159 patients harboring ESR1 mutations (ESR1-mut) who were treated with CDK4/6i for 12+ months, elacestrant showed a median PFS of 8.6 months in 78 patients vs. 1.9 months for standard of care in 81 patients, a 59% reduction in the risk of progression or death.

“These results further highlight elacestrant’s potential to change the treatment paradigm of ER+, HER2- advanced or metastatic breast cancer,” Menarini Group CEO Elcin Barker Ergun said in a statement. The drug is already under FDA Priority Review, with a target PDUFA decision date of February 17.

Another oral SERD breast cancer candidate showing positive results in advanced trials is AstraZeneca’s camizestrant. AstraZeneca presented data at SABCS from the Phase II SERENA-2 trial (NCT04214288) showing a statistically significant and clinically meaningful PFS improvement at both 75-mg and 150-mg dose levels versus the company’s Faslodex® (fulvestrant) 500-mg dose in post-menopausal patients with ER+ locally advanced or metastatic breast cancer, previously treated with endocrine therapy.

Also at SABCS, Arvinas presented data for the PROTAC® ER protein degrader ARV-471—which the company is co-developing with Pfizer—from the Phase II VERITAC cohort expansion portion of a larger Phase I/II trial (NCT04072952) assessing the drug alone and with palbociclib. The data showed antitumor activity for ARV-41 monotherapy in all 71 CDK4/6 inhibitor-pretreated patients, as measured by a clinical benefit rate (CBR) of 38% in all patients and 51.2% in 41 patients with mutant ESR1 tumors. CBR is defined as rate of confirmed complete response, confirmed partial response, or stable disease at 24 or more weeks.

ARV-471 also showed preliminary median PFS of 3.7 months, a key secondary endpoint of SERENA-2, in all evaluable patients and 5.7 months in all patients with mutant ESR1 tumors. ARV-471 is being developed for patients with locally advanced or metastatic ER+/HER2- breast cancer.

As for Olema and OP-1250, in addition to its efficacy data, the company is promoting positive safety and tolerability data for the SERD/CERAN. Across the 12 patients studied in its Phase Ib trial, the combination of up to 120 mg of OP-1250 with 125 mg of palbociclib was found to be safe and well-tolerated with no drug-drug interaction, no induced metabolism of palbociclib, and consistent with observed monotherapy OP-1250 exposure levels.

The OP-1250/palbociclib combination showed no dose-related increase in the incidence or severity of adverse events. The neutropenia events observed were consistent with the expected profile of palbociclib plus endocrine therapy.

Beyond second/third line

“This initial data indicates that we will have the tolerability and PK to pursue that that in an even larger market than the second- and third-line setting,” Olema CEO Bohen said.

A first line combination trial of OP-1250 is expected to occur two to three quarters after the release of additional second- and third-line data, which likely takes the trial into 2024. “What we don’t know is, will that first line trial be in combination with palbociclib, or in combination with ribociclib, because we’re generating data for both,” Bohen said.

Ribociclib is a CDK 4/6 inhibitor marketed by Novartis as Kisqali®, indicated for adults with HR+/HER2- advanced or metastatic breast cancer in combination with an aromatase inhibitor or fulvestrant as initial endocrine-based therapy. Kisqali is one of two Novartis drugs for which Olema is assessing OP-1250 in a Phase Ib combination therapy trial (NCT05508906); the other is alpelisib, (Piqray®), a phosphoinositide 3-kinase (PI3K) alpha inhibitor indicated in combination with fulvestrant for postmenopausal women and men with HR+/HER2- PIK3CA-mutated, advanced or metastatic breast cancer.

OP-1250 last fall showed positive early monotherapy data in a Phase I/II study (NCT04505826). In a presentation at the 34th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics (ENA 2022) in Barcelona, Olema showed that among 57 efficacy-evaluable patients, 41% showed anti-tumor activity such as reduction in target lesions and evidence of activity in both wild-type and mutant estrogen receptors across both the 60-mg and 120-mg doses. Six patients showed partial responses, including four confirmed partial responses and two unconfirmed partial responses awaiting confirmation via follow-up scan.

Also, according to Olema, OP-1250 was well tolerated at both doses with no dose-limiting toxicities. Additional data is set to be presented later this year, with a monotherapy Phase III trial expected in mid-2023. “We believe Olema’s OP-1250 monotherapy efficacy data continue to hold up well in early data and have the chance to improve as the data mature,” added Maughan of Canaccord Genuity.

Publicly-traded Olema finished the third quarter with a net loss of $22.72 million, compared with a net loss of $17.71 million in Q3 2021, due to rising expenses related to continued development of OP-1250, increased R&D spending, and higher general and administrative costs.

Olema finished Q3 2022 with $222.6 million in cash, cash equivalents, and marketable securities. While that is 27% below the $305.95 million reported at the end of the third quarter of 2021, “It gives us a comfortable runway into the second half of 2024,” Bohen said.

Headquartered in San Francisco with operations in Cambridge, MA, Olema currently employs about 70 people, with plans to expand that headcount during 2023.

“We really haven’t forecast the guidance for growth at this point in time, but we definitely are growing,” Bohen said. “We have to get ready to do a pivotal trial program, which is the obviously the biggest catalyst for growth.”

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