palazestrant (OP-1250) / Olema Pharma - LARVOL DELTA

OPERA-02: A phase 3 study of palazestrant plus ribociclib as first-line treatment of ER+, HER2- advanced breast cancer. (ASCO 2026) - P3 | " OPERA-02 (NCT07085767) is a phase 3, international, multicenter, randomized, double-blind, study designed to evaluate the efficacy and safety of palazestrant plus ribociclib versus letrozole plus ribociclib in the first line treatment of pts with ER+, HER2- ABC. Pre- or perimenopausal women and men must receive gonadotropin-releasing hormone (GnRH) agonists for gonadal function suppression. The study has been recruiting globally since November 2025."

Clinical • Metastases • P3 data • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

OP-1250-003: Phase 1b Study of OP-1250 (Palazestrant) in Combination With Ribociclib, Alpelisib, Everolimus, or Atirmociclib in ER+, HER2- Breast Cancer (clinicaltrials.gov) - P1 | N=190 | Active, not recruiting | Sponsor: Olema Pharmaceuticals, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

A phase Ib/II study of palazestrant (OP-1250) in combination with ribociclib in patients with estrogen receptor-positive human epidermal growth factor receptor 2-negative (ER+, HER2-) metastatic breast cancer (ESMO-BC 2024) - P1 | "Twenty-seven pts (82%) received prior CDK4/6i: 24 prior palbociclib, 5 prior ribociclib and 4 prior abemaciclib; 7 pts (21%) received two prior lines of CDK4/6i. Antitumor activity and clinical benefit, including in heavily pretreated patients, were observed. Updated data will be presented."

Clinical • Combination therapy • Metastases • P1/2 data • Anemia • Breast Cancer • Fatigue • Hematological Disorders • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Neutropenia • Oncology • Solid Tumor • ER • HER-2

OPERA-02: a phase 3 randomized, double-blind, active-controlled study of palazestrant with ribociclib versus letrozole with ribociclib for the first-line treatment of ER+, HER2- advanced breast cancer (SABCS 2025) - "Secondary endpoints include PFS by a blinded-independent review committee, OS, overall response rate, clinical benefit rate, duration of response, safety, pharmacokinetics and health-related patient-reported outcomes. The study is conducted globally."

Clinical • Metastases • P3 data • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

Palazestrant (OP-1250) plus ribociclib in patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+, HER2-) advanced breast cancer (ABC) (ESMO 2025) - P1 | "75% pts had prior ET, 39% had prior fulvestrant and 71% pts had prior CDK4/6i for ABC (16% had two prior CDK4/6i). Conclusions Palazestrant and ribociclib safety were consistent with the previous reports for each drug in ABC and with robust efficacy in all pts and in those with prior CDK4/6i. A first-line phase 3 trial (OPERA-02) is planned."

Clinical • Metastases • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • HER-2

Updated results from the phase I/II study of OP-1250, an oral complete estrogen receptor (ER) antagonist (CERAN) and selective ER degrader (SERD) in patients (pts) with advanced or metastatic ER-positive, HER2-negative breast cancer (ESMO 2023) - P2 | "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."

Clinical • Metastases • P1/2 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • PIK3CA

Palazestrant: Regulatory approval and launch in US for 2/3L ER+/HER2- metastatic breast cancer (based on OPERA-01 trial) in 2028 (Olema Oncology) - Corporate Presentation

FDA approval • Launch US • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Negative Breast Cancer • Oncology

OPERA-01: OP-1250 (Palazestrant) vs. Standard of Care for the Treatment of ER+/HER2- Advanced Breast Cancer (clinicaltrials.gov) - P3 | N=510 | Active, not recruiting | Sponsor: Olema Pharmaceuticals, Inc. | Trial completion date: Sep 2027 ➔ Feb 2028 | Trial primary completion date: Jun 2026 ➔ Oct 2026 | Recruiting ➔ Active, not recruiting

Enrollment closed • Monotherapy • Trial completion date • Trial primary completion date • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

Anticipated Upcoming Events (GlobeNewswire) - "(i) Initiate enrollment in the Phase 1b/2 study evaluating OP-3136 in combination with darolutamide in mCRPC in collaboration with Bayer in the fourth quarter of 2026; (ii) Report top-line data from the pivotal Phase 3 OPERA-01 trial in the first quarter of 2027."

New P1/2 trial • P3 data: top line • Castration-Resistant Prostate Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Negative Breast Cancer

Recent Progress (GlobeNewswire) - "(i) Completed enrollment in the pivotal Phase 3 OPERA-01 trial of palazestrant as a monotherapy in patients with second or third-line estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer (MBC)...; (ii) Completed enrollment in the Phase 1b/2 study of palazestrant in combination with atirmociclib in ER+/HER2- MBC."

Enrollment closed • Estrogen Receptor Positive Breast Cancer • HER2 Negative Breast Cancer

A phase 1, first-in-human study of OP-3136, a novel oral selective KAT6A/B inhibitor, as monotherapy in advanced solid tumors and in combination with endocrine therapy in ER+, HER2− advanced breast cancer (ABC): Preliminary results. (ASCO 2026) - P1 | "OP-3136 demonstrated a manageable safety profile and favorable PK, both as monotherapy and in combination with fulvestrant. Preliminary evidence of antitumor activity in ER+ HER2- ABC and mCRPC was observed in these heavily pretreated pts. Dose escalation and enrollment in combination with fulvestrant or palazestrant are ongoing and updated data will be presented."

Combination therapy • First-in-human • Metastases • Monotherapy • P1 data • Breast Cancer • Castration-Resistant Prostate Cancer • Estrogen Receptor Positive Breast Cancer • Genito-urinary Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Leukopenia • Lung Cancer • Neutropenia • Non Small Cell Lung Cancer • Oncology • Prostate Cancer • Solid Tumor • ER • HER-2 • KAT6A

Palazestrant: Regulatory submission, approval and launch in US for 2/3L ER+/HER2- metastatic breast cancer (based on OPERA-01 trial) in 2027 (Olema Oncology) - Corporate Presentation: Regulatory approval and launch in US for ER+/HER2- metastatic breast cancer (based on OPERA-02 trial in combination with ribociclib) in 2029

FDA approval • FDA filing • Launch US • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Negative Breast Cancer • Oncology

OPERA-02 Trial-in-Progress Poster Presentation Details (GlobeNewswire) - "Olema will also present a trial-in-progress poster for the Phase 3 OPERA-02 trial of palazestrant in combination with ribociclib in frontline ER+/HER2- metastatic breast cancer."

Trial status • Estrogen Receptor Positive Breast Cancer • HER2 Negative Breast Cancer

OPERA-02: A PHASE 3 RANDOMIZED, DOUBLE-BLIND, ACTIVE-CONTROLLED STUDY OF PALAZESTRANT WITH RIBOCICLIB VERSUS LETROZOLE WITH RIBOCICLIB FOR THE FIRST-LINE TREATMENT OF ER+, HER2– ADVANCED BREAST CANCER (BMC-BBCS 2026) - P3 | "Pre- or perimenopausal women and men must receive gonadotropin-releasing hormone agonists. The study is recruiting globally."

Clinical • Metastases • P3 data • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • HER-2

OPERA-02: a phase 3 randomized, double-blind, active-controlled study of palazestrant with ribociclib versus letrozole with ribociclib for the first-line treatment of ER+, HER2– advanced breast cancer (BMC-BBCS 2026) - No abstract available

Clinical • Metastases • P3 data • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

Anticipated Upcoming Events: (Olema Oncology Press Release) - "Present initial clinical data from the Phase 1 study evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of OP-3136 in a poster presentation at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting...Present trial-in-progress poster for the ongoing pivotal Phase 3 OPERA-02 trial evaluating palazestrant in combination with ribociclib in frontline ER+/HER2- metastatic breast cancer at ASCO...Report top-line data from the pivotal Phase 3 OPERA-01 trial of palazestrant as a monotherapy in second- and third-line ER+/HER2- metastatic breast cancer in the fall of 2026."

P1 data • P3 data: top line • Trial status • Estrogen Receptor Positive Breast Cancer • HER2 Negative Breast Cancer

Recent Progress (Olema Oncology Press Release) - "Continued enrollment in the pivotal Phase 3 OPERA-02 trial evaluating palazestrant in combination with ribociclib in frontline ER+/HER2- advanced or metastatic breast cancer; Advanced enrollment in the Phase 1b/2 study evaluating palazestrant in combination with atirmociclib in ER+/HER2- metastatic breast cancer in collaboration with Pfizer."

Enrollment status • Estrogen Receptor Positive Breast Cancer • HER2 Negative Breast Cancer

Palazestrant directly recruits the corepressor protein NCoR1 in vitro leading to complete antagonism of estrogen receptor alpha (AACR 2026) - "Contrarily, selective estrogen receptor modulators (SERMs) such as 4-OH-tamoxifen and vepdegestrant either do not induce recruitment or are incomplete recruiters, in line with previous data indicating that SERMs are not complete antagonists...CERAN molecules palazestrant and fulvestrant consistently demonstrate greater suppression of GREB1 and PGR as compared to SERMs in both ESR1 wildtype and mutant ER+ breast cancer models.Functionally, treatment with palazestrant leads to antiproliferative activity in ER+ breast cancer models comparable or superior to investigational and approved anti-estrogens...When cells are not stimulated with E2, SERMs like tamoxifen demonstrate induction of cell proliferation where CERANs do not. Palazestrant is a promising therapeutic strategy for treating ER+/HER2- breast cancer patients and is being evaluated clinically, both as monotherapy and combination."

Preclinical • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • NCOR1

OPERA-02: Palazestrant in Combination With Ribociclib for the First-line Treatment of ER+/HER2- Advanced Breast Cancer (clinicaltrials.gov) - P3 | N=1000 | Recruiting | Sponsor: Olema Pharmaceuticals, Inc. | N=360 ➔ 1000

Enrollment change • Trial initiation date • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

OPERA-02: Palazestrant in Combination With Ribociclib for the First-line Treatment of ER+/HER2- Advanced Breast Cancer (clinicaltrials.gov) - P3 | N=360 | Recruiting | Sponsor: Olema Pharmaceuticals, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

OPERA-01: OP-1250 (Palazestrant) vs. Standard of Care for the Treatment of ER+/HER2- Advanced Breast Cancer (clinicaltrials.gov) - P3 | N=510 | Recruiting | Sponsor: Olema Pharmaceuticals, Inc. | N=382 ➔ 510

Enrollment change • Monotherapy • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

Phase 1 Study of OP-3136 in Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1 | N=180 | Recruiting | Sponsor: Olema Pharmaceuticals, Inc. | N=48 ➔ 180

Enrollment change • First-in-human • Breast Cancer • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Prostate Cancer • Solid Tumor • ER • HER-2

Palazestrant, a CERAN, in combination with OP-3136, a KAT6 inhibitor, synergistically downregulates cell proliferation and metastasis related gene signatures (AACR 2026) - "The transcriptional changes align with enhanced anti-tumor efficacy and establish a mechanistic rationale for this combination over fulvestrant in ER+ breast cancer. The palazestrant–OP-3136 combination is currently being evaluated in a phase I clinical trial in ER+/HER2– metastatic breast cancer patients."

Combination therapy • Gene Signature • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • E2F1 • FOXA1 • GATA3 • HER-2 • KAT6A • KAT6B • TNFA

Olema Oncology to Present Initial Clinical Data for OP-3136 at the 2026 ASCO Annual Meeting (GlobeNewswire) - "Olema Oncology...will present initial clinical data from the Phase 1 study of OP-3136 in a poster presentation....The Company will also present a trial-in-progress poster for the Phase 3 OPERA-02 trial."

P1 data • Trial status • Estrogen Receptor Positive Breast Cancer • HER2 Negative Breast Cancer

Phase 1 Study of OP-3136 in Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1 | N=48 | Recruiting | Sponsor: Olema Pharmaceuticals, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • First-in-human • Breast Cancer • HER2 Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Prostate Cancer • Solid Tumor • ER • HER-2