Lay Description

postMONARCH is a Phase 3, global, multicenter, randomized, double-blind, placebo-controlled

study in participants with HR+, HER2- advanced or metastatic breast cancer. This study will

enroll adults who experienced disease progression on a CDK4 & 6 inhibitor and an AI in the

first-line setting or relapse on/after a CDK4 & 6 inhibitor with ET in the adjuvant setting.


  • Cancers and Other Neoplasms
IRB Number
NCT Number registration not required
Open to Enrollment


Eligible Ages
18 and above
Eligible Genders
Accepts Healthy Volunteers

Inclusion Criteria

Participants are eligible to be included in the study only if all the following criteria apply:
1. ≥18 years of age (or of an acceptable age according to local regulations, whichever is
older) at the time of signing the informed consent.
Type of Participant and Disease Characteristics
2. Have a diagnosis of HR+, HER2- breast cancer. To fulfill the requirement of
a) HR+ disease: must express, by immunohistochemistry (IHC), at least 1 of
the hormone receptors (estrogen receptor [ER] or progesterone receptor
[PgR]) as defined in the relevant American Society of Clinical Oncology
(ASCO)/College of American Pathologists (CAP) Guidelines (Hammond
et al. 2010).
b) HER2- disease: must not demonstrate, at initial diagnosis or upon subsequent
biopsy, overexpression of HER2 by either IHC or in-situ hybridization as defined
in the relevant ASCO/CAP Guidelines (Wolff et al. 2018).
3. Have either advanced disease not amenable to curative surgical treatment or metastatic
4. Have radiologic evidence of disease progression or recurrence either
a) On treatment with a CDK4 & 6 inhibitor (palbociclib, ribociclib, or abemaciclib)
plus AI as initial therapy for advanced disease, or
b) On/after treatment with a CDK4 & 6 inhibitor (palbociclib, ribociclib, or
abemaciclib) plus ET administered as adjuvant therapy for early-stage breast
5. Have either measurable disease or non-measurable but evaluable disease. Measurable,
non-measurable, and evaluable disease are defined according to the Response Evaluation
Criteria in Solid Tumors (RECIST Version 1.1 [v1.1], Eisenhauer et al. 2009).
6. Have a performance status (PS) of 0 or 1 on the Eastern Cooperative Oncology Group
(ECOG) scale (Oken et al. 1982).
7. Must be deemed appropriate for treatment with ET.
8. Have discontinued previous treatments and recovered from the acute effects of therapy to
at least Grade 1, except for residual alopecia and peripheral neuropathy, with the
following therapy washout periods required prior to receiving study drug:
Previous Treatment Length of Time Prior to First Dose of Study Drug
CDK4 & 6 inhibitor 7 days
Endocrine therapy  days or 5 half-lives, whichever is shorter
Radiotherapy  days
Major surgery 14 days
9. Have adequate organ function, as defined below:
System Laboratory Value
ANC 1.5×109/L
Platelets 100×109/L
Hemoglobin 8 g/dL
Note: transfusions to increase a patient’s hemoglobin or initiation of erythropoietin or G-CSF therapy to
meet enrollment criteria are not allowed in the 14 days preceding the first dose of study drug.
Total bilirubin
Participants with Gilbert’s syndrome with a total
bilirubin ≤2.0×ULN and direct bilirubin within
normal limits are permitted
Abbreviations: ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate
aminotransferase; G-CSF = granulocyte colony-stimulating factor; ULN = upper limit of normal.
Sex and Contraceptive/Barrier Requirements
10. Males and females may participate.
a. Male participants
Must agree to use hormone suppression (received monthly and initiated at least 28 days
prior to Cycle 1 Day 1) with a gonadotropin-releasing hormone agonist such as goserelin
or leuprolide.
b. Female participants
Must have postmenopausal status due to either surgical/natural menopause or ovarian
suppression (received monthly and initiated at least 28 days prior to Cycle 1 Day 1) with
a gonadotropin-releasing hormone agonist, such as goserelin or leuprolide.
Postmenopausal status due to surgical/natural menopause requires at least 1 of the
a. prior bilateral oophorectomy
b. age ≥55 years and amenorrhoeic for at least 12 months or with a diagnosis of
c. age ≥40 and <55 years, amenorrhoeic for at least 12 months (in the absence of
chemotherapy, tamoxifen, toremifene, or ovarian suppression), and FSH in the
postmenopausal range (≥40 mIU/mL)
Contraceptive/Barrier Requirements
11. Contraceptive use should be consistent with local regulations regarding the methods of
contraception for those participating in clinical studies.
a. Male participants
No male contraception is required except in compliance with specific local government
study requirements. Males are eligible to participate if they agree to refrain from donating
sperm during the treatment period. Contraception requirements for male participants
receiving fulvestrant should follow the approved local label.
b. Female participants
 Women of childbearing potential (WOCBP) must test negative for pregnancy prior to
initiation of treatment with a negative serum pregnancy test at the screening visit,
followed by a negative urine pregnancy test within 48 hours prior to first exposure to
study drug, and
 WOCBP must agree to use 2 forms of effective contraception where at least one form
must be highly effective (less than 1% failure rate) to prevent pregnancy while
receiving study treatment, for 3 weeks after the last dose of blinded study drug and
for 2 years after the last dose of fulvestrant (or according to local approved fulvestrant
Note: WOCBP who are completely abstinent or in a same-sex relationship as part of their
preferred and usual lifestyle must agree to either remain abstinent or refrain from sexual
intercourse with males.
Please refer to Section 10.4 (Appendix 4) for definitions and additional guidance related to
Informed Consent
12. Capable of giving signed informed consent as described in Appendix 1, which includes
compliance with the requirements and restrictions listed in the informed consent form
(ICF) and in this protocol.
Other Inclusions
13. Willing to participate for the duration of the study and to follow study procedures
including use of Sponsor-provided electronic devices to collect patient reported outcomes
14. Able to swallow capsules and tablets

Exclusion Criteria

Participants are excluded if any of the following apply:
Medical Conditions
15. Have visceral crisis, lymphangitic spread, or leptomeningeal carcinomatosis. Visceral
crisis is not the mere presence of visceral metastases but implies severe organ
dysfunction as assessed by symptoms and signs, laboratory studies, and rapid progression
of the disease.
16. Have symptomatic or untreated central nervous system (CNS) metastasis. Participants
with treated CNS metastases are eligible if
a. they completed prior therapy (including radiation and/or surgery) ≥28 days prior
to first dose of study treatment, and
b. they have not received corticosteroids and/or anticonvulsants for at least 14 days
prior to first dose of study treatment, and
c. their disease is both asymptomatic and radiographically stable by repeat imaging
for at least 28 days prior to consent (repeat imaging should be performed during
study screening).
17. Have a history within the last 12 months of any of the following conditions: syncope of
cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not
limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest.
Exception: patients with controlled atrial fibrillation for >30 days prior to randomization
are eligible.
18. Have serious preexisting medical condition(s) that, in the judgment of the investigator,
would preclude participation in this study (such as severe renal impairment [for example,
estimated creatinine clearance <30 mL/min], active symptoms of ILD/pneumonitis,
severe dyspnea at rest or requiring oxygen therapy, history of major surgical resection
involving the stomach or small bowel, or preexisting Crohn’s disease or ulcerative colitis
or a preexisting chronic condition resulting in clinically significant diarrhea).
19. Have a history of any other cancer (except nonmelanoma skin cancer or carcinoma in-situ
of the cervix), unless in complete remission with no therapy for a minimum of 3 years
20. Have a known active systemic infection (for example, bacterial, fungal, or detectable
viral infection requiring systemic therapy).
a) Participants with uncontrolled human immunodeficiency virus (HIV) infection or an
acquired immunodeficiency syndrome (AIDS) defining illness are not eligible.
Participants with known HIV infection and CD4+ T-cell (CD4+) counts ≥350
cells/μL are eligible.
b) Participants with hepatitis B are not eligible unless viral load is below the level of
c) Participants with known hepatitis C are not eligible unless they have completed
curative anti-viral therapy and viral load is below the level of quantification.
d) Screening for HIV, coronavirus disease 2019 (COVID-19), hepatitis B, or hepatitis C
is not required.
Prior/Concomitant Therapy
21. Have received any intervening line of systemic therapy between disease
recurrence/progression and study screening.
22. Have received more than 1 line of therapy for advanced or metastatic disease.
23. Have received prior treatment with chemotherapy for MBC.
24. Have received prior treatment with any CDK4 & 6 inhibitor-based regimen other than
those specified. Prior treatment with a CDK4 & 6 inhibitor in more than 1 setting (e.g.,
adjuvant and then metastatic) is not permitted.
25. Have received prior treatment with fulvestrant, any investigational ER-directed therapy
(including SERDs and non-SERDs), any PI3K-, mTOR-, or AKT-inhibitor.
26. Have known pathogenic germline mutations appropriate for a PARP inhibitor, in regions
where these therapies are approved and available, per investigator’s discretion.
27. Have initiated bisphosphonates or approved RANK ligand (RANK-L) targeted agents
(e.g. denosumab) <7 days prior to randomization.
28. Are receiving concurrent exogenous reproductive hormone therapy (for example, birth
control pills, hormone replacement therapy, or megestrol acetate). Appropriate washout
period between last dose and randomization is up to the investigator’s medical judgment
(for example, applying 7 days or 5 times the half-life elimination rule). Note: topical
vaginal estrogen therapy is permitted if all other non-hormonal options are exhausted.
29. Have received an autologous or allogeneic stem cell transplant.
Prior/Concurrent Clinical Study Experience
30. Are currently enrolled in any other clinical study involving an investigational product or
any other type of medical research judged not to be scientifically or medically compatible
with this study.
Other Exclusions
31. Are pregnant or breastfeeding.
32. Have known or suspected hypersensitivity reactions or intolerance to study drug or to any
of the excipients (e.g., lactose), unless deemed appropriate by the investigator.

Study Design

Arm Groups

Study Contact

Frances Crawford
(210) 450-5037

Sonia Creighton
(210) 450-1366

Myrna Montenegro
(210) 450-5954

Courtney Nichols
(210) 450-1794

Mailbox Ctrc Regulatory Affairs

Kathleen Rodriguez
(210) 450-1365

Benjamin Schleif
(210) 450-1366

Morgan Seekatz
(210) 450-1133

Principal Investigator
Virginia Kaklamani