palazestrant (OP-1250)

P1, N=90, Recruiting, Olema Pharmaceuticals, Inc. | Phase classification: P1b --> P1 | N=60 --> 90

OP-1250 combines well with cyclin-dependent kinase 4 and 6 inhibitors in xenograft studies of ER+ breast cancer models and effectively shrinks intracranially implanted tumors, resulting in prolonged animal survival. With demonstrated preclinical efficacy exceeding fulvestrant in wild-type models, elacestrant in ESR1-mutant models, and tamoxifen in intracranial xenografts, OP-1250 has the potential to benefit patients with ER+ breast cancer.

P3, N=510, Recruiting, Olema Pharmaceuticals, Inc. | Not yet recruiting --> Recruiting

The OPERA-01 trial is an international, multicenter, randomized, open-label, phase 3 clinical trial comparing the efficacy and safety of palazestrant as a single agent to standard-of-care ET (fulvestrant, anastrozole, letrozole, or exemestane) in pts with ER-positive, HER2-negative advanced BC or MBC that has relapsed or progressed on 1 or 2 prior lines of ET for MBC, which includes a CDK4/6 inhibitor. Secondary endpoints include overall survival, antitumor activity (objective response rate, clinical benefit rate, and duration of response), safety, patient-reported outcomes, and PK in pts with and without ESR1 mutations. The study is planned to be conducted globally.

Addition of the PIK3 inhibitor alpelisib to ET significantly improved progression-free survival in pts with PIK3CA-mutated, ER-positive, HER2-negative MBC, and alpelisib + fulvestrant is the standard of care for second or later-line treatment. In this ongoing study, palazestrant in combination with ribociclib or alpelisib was well tolerated, and enrollment to the palazestrant 120 mg dose with ribociclib or alpelisib is ongoing. No new safety signals were observed for the 3 drugs, and no clinically significant DDIs were observed between palazestrant and ribociclib or alpelisib at the doses evaluated. Exposure of each drug was consistent with observed monotherapy exposure levels.

Palazestrant and palbociclib dosed in combination were well tolerated with a safety profile consistent with the individual profiles of each drug as monotherapy, and there were no DDIs. Tumor responses and clinical benefit were observed in this population of patients, including those who received prior CDK4/6 inhibitors. Expanding on our previous report, these data provide the rationale to continue advancing the clinical development of palazestrant with the approved dose of palbociclib.

OP-1250 did not affect palbociclib PK and no DDIs have been observed with this combination. OP-1250 and palbociclib combination was well tolerated, safety was consistent with individual profiles of each drug as a monotherapy. Tumor responses were observed in this heavily pretreated population.

P3, N=510, Not yet recruiting, Olema Pharmaceuticals, Inc.

Conclusions OP-1250 (120 mg qd) was well tolerated with promising efficacy in heavily pretreated pts, including pts progressing on fulvestrant and CDK4/6i. A phase 3 monotherapy study in metastatic BC (second/third line) is planned in 2023.

Enrollment at approximately 20 sites in the United States and Australia is ongoing. Clinical trial information: NCT05508906.

Updated data will be presented. (NCT0526610).

In the first three cohorts of OP-1250 and palbociclib, the combination was well tolerated and no DLTs occurred. There were no clinically significant DDIs observed between OP-1250 and palbociclib at the doses evaluated and exposure of each drug was consistent with observed monotherapy exposure levels. Dose escalation of OP-1250 continues to 120 mg, to be followed by dose expansion.

P1b, N=60, Recruiting, Olema Pharmaceuticals, Inc. | Not yet recruiting --> Recruiting

OP-1250 was well tolerated and showed promising safety and efficacy in Phase 1b pts treated at 60 mg and 120 mg daily. Based on safety and pharmacokinetic data, a RP2D will be selected. A Phase 2 evaluation will be initiated, and a Phase 3 monotherapy study is planned for 2023.

P1b, N=60, Not yet recruiting, Olema Pharmaceuticals, Inc.

P1, N=30, Not yet recruiting, Olema Pharmaceuticals, Inc.

OP-1250 is continuing evaluation in a phase I/II study. The population enrolled reflects the evolving standard of care in that all pts received prior CDK4/6 inhibitors and the majority also received fulvestrant. OP-1250 is well tolerated with a favorable PK across dose levels ensuring target coverage throughout the dosing interval.

P1, N=30, Not yet recruiting, Olema Pharmaceuticals, Inc.

No abstract available

To conduct a preliminary assessment of the antitumor activity (ORR) of OP-1250 in subjects with HR+, HER2- MBC who have progressed on endocrine therapy and have CNS disease. Assessment of response will be determined according to RECIST 1.1 and Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria Correlative Science To determine biomarker expression, such as, ER, PR, Ki67 and others in the most recently obtained archival tumor tissue sample To evaluate whether ESR1 in circulating tumor DNA (ctDNA) can be correlated with response and/or activity of OP-1250 To examine ctDNA pre- and post-therapy for mutESR1 and PIK3CA variants, and other relevant markers For more information, please contact clinical@olemapharma.com