Cohort A – Breast Cancer:

1. Has a diagnosis of HR+/HER2- invasive breast carcinoma that is either locally advanced disease not amenable to resection with curative intent (herein called unresectable) or metastatic disease not treatable with curative intent.

2. Has locally confirmed HR+ (defined as ER and/or PgR ≥1%) and HER2- invasive breast cancer (defined as IHC 0, IHC 1+ or IHC 2+/ISH-) according to the most recent ASCO/CAP guidelines on the most recent biopsy.

ER+ and/or PgR+ as determined by local testing on a tumor biopsy obtained preferably from a distant metastasis site or a local recurrence before randomization based on the most recent ASCO/CAP guidelines. Tumor will be considered HR+ if the tumor shows ≥1% expression of ER and/or PgR, respectively.

HER2- as determined by local testing on a tumor biopsy obtained preferably from a distant metastasis site or a local recurrence before randomization based on the most recent ASCO/CAP guidelines. Tumor will be considered HER2- defined as IHC 0, IHC 1+ or IHC 2+/ISH-. Note: It is preferred that this same sample be used to submit to central lab for HR/HER2 status.

3. Has experienced disease progression on or after at least 1 prior endocrine-based therapy in the metastatic setting:

a. 1 line of an approved combination of ET plus CDK4/6 inhibitor in the metastatic setting with duration on CDK4/6 inhibitor of ≥24 months

OR

b. 2 or more lines of ETs in the metastatic setting, where the patient did not tolerate CDK4/6 inhibitor or CDK4/6 inhibitor was not available. Note: Prematurely discontinued CDK4/6 inhibitor in combination with ET does not need to be the most recent therapy in the noncurative setting. 

Note: Participant who received CDK4/6 inhibitor in combination with ET in the adjuvant setting will only be eligible if recurrence was >24 months after the last CDK4/6 inhibitor dose AND at least 1 additional line of ET is given in the metastatic setting.

Note: Single-agent CDK4/6 inhibitors are not considered a line of ET.

Note: Changes in dosing schedules, or discontinuation and retreatment with the same combinations of drugs or same class of drugs (ie, changing from 1 aromatase inhibitor to another) in the absence of radiographic disease progression will not be considered separate lines of previous ET.

Note: If an attempt to downstage a locally advanced tumor with neoadjuvant ET was made in the absence of metastatic breast cancer and the tumor operated upon with curative intent, then this does not count as a line of therapy in the noncurative setting. However, if the tumor remained inoperable with curative intent, this endocrine treatment is included as a line of therapy in the noncurative setting.

Note: Prior treatment with mTOR, PI3K and/or AKT inhibitors is allowed.

4. Provides a newly obtained biopsy sample from a locally advanced inoperable lesion or from a metastatic lesion. If the last obtained core biopsy was obtained after disease progression on most recent therapy, a new biopsy is not required. Sample should preferably consist of multiple cores from a lesion not previously irradiated. If a new biopsy is required, it needs to be performed before baseline tumor scan assessment. FFPE tissue blocks are preferred to slides.

Note: Please refer to Section 8.1.13 for further details.

5. Is eligible for additional ET with fulvestrant or exemestane as per local investigator assessment.

Premenopausal and perimenopausal (ie, those that do not meet the criteria for postmenopausal as defined in Appendix 5) participants assigned female sex at birth and participants assigned male sex at birth are eligible if amenable to treatment with an LHRH or GnRH agonist. Participants are to have commenced concomitant treatment with GnRH or LHRH agonists at least 4 weeks prior to Cycle 1, Day 1 and must be willing to continue it for the duration of the study.

6. If receiving bisphosphonates, RANK ligand inhibitors, or romosozumab, with stable doses for ≥4 weeks prior to the date of randomization, the participant may continue receiving this therapy during the study treatment. If participant needs to initiate these agents during the Screening period, a bone scan to evaluate bone disease should be performed prior to randomization.

Cohort B – Ovarian Cancer:

7. Has histologically confirmed high-grade epithelial (including high-grade serous or predominantly serous, high-grade endometrioid, malignant mixed Müllerian tumors [carcinosarcoma], or clear cell) ovarian, fallopian tube, or primary peritoneal carcinoma. 

8. Has received between 4 to 8 cycles of platinum-based doublet chemotherapy in 3L setting for ovarian cancer.

The interval between the last dose of 3L chemotherapy and randomization must be ≤9 weeks.

Any adjuvant ± neoadjuvant therapy is considered 1 line of therapy.

Any chemotherapy regimen change (substitution or change in entire regimen) due to toxicity in the absence of disease progression will be considered part of the same line of therapy.

Participants may have received prior anti-PD-1/anti-PD-L1. These will count as a line of therapy if given as a single agent and will not be considered a separate line of therapy if given as maintenance treatment.

9. Has platinum-sensitive epithelial ovarian cancer, defined as first recurrence of epithelial ovarian, primary peritoneal or fallopian tube carcinoma with radiographic evidence of disease progression >180 days after the last dose of 2L platinum-based chemotherapy for ovarian cancer.

10. Has radiographic response or SD as assessed by the investigator to 3L induction chemotherapy at time of Screening. Note: Participants with fluid-only disease (eg, pleural effusion or ascites, and no other radiographically apparent lesions) must have cytologic confirmation of malignancy.

11. According to investigator assessment, PARPi 3L maintenance treatment is not the preferred option for the participant.

12. A participant is eligible to participate regardless of ovarian cancer biomarker status; however, participants with known BRCAm/HRD+ ovarian cancer must have previously received PARPi as 1L or 2L maintenance treatment.

Cohort C – Endometrial Cancer:

13. Histologically confirmed diagnosis of primary advanced or recurrent low-grade endometrioid carcinoma (eg, FIGO Grade 1/2, or well/moderately differentiated).

14. Has a locally determined pMMR status determined by immunohistochemistry. Note: the local MMR assay should assess MSH6, PMS2, MSH2 and MLH1. pMMR is defined as all 4 proteins expressed.

15. Wildtype expression of p53 as determined by local assessment using an IHC or molecular test.

16. Treatment naïve or has received up to 1 prior line of platinum-based therapy in either the advanced/metastatic OR adjuvant/neoadjuvant setting. 

Nonplatinum-based therapy: Prior use of PD-1/PD-L1 inhibitors or other naked Abs is allowed if they were given in combination with platinum-based chemotherapy. Other prior nonplatinum-based systemic therapy is not allowed (examples include but are not limited to single-agent chemotherapy, hormonal therapy, PARP inhibitors or other targeted therapy, ADCs, investigational agents, or use of PD-1/PD-L1 inhibitors after progression on platinum-based chemotherapy).

Neoadjuvant/adjuvant therapy: Instances in which both adjuvant and neoadjuvant systemic platinum-based chemotherapy are used will be counted as 1 line of chemotherapy.

Radiation therapy: Prior neoadjuvant/adjuvant chemotherapy may be given as treatment involving chemotherapy alone, concurrent chemoradiation, or as part of a sequential approach such as in a regimen involving concurrent chemoradiation followed by chemotherapy. In addition to 1 prior line of platinum-based chemotherapy, patients may have received prior radiation with or without radiosensitizing chemotherapy if >2 weeks before the start of study intervention. Participants must have recovered adequately from all radiation-related toxicities (as determined by the investigator), not require systemic corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.

17. Per investigator assessment, patient is a candidate for hormonal therapy based on local practice and/or guidelines.

All Cohorts Demographics

18. Is at least 18 years of age at the time of providing the informed consent. Assigned Female Sex at Birth

19. A participant assigned female sex at birth is eligible to participate if not breastfeeding during the study intervention period and for at least 7 days after the last dose of study intervention MK-5684.

20. A POCBP is eligible to participate if not pregnant and if a negative highly sensitive pregnancy test (urine or serum), as required by local regulations, has been obtained within 24 hours (for a urine test) or 72 hours (for a serum test) before the first dose of study intervention. If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. Additional requirements for pregnancy testing during and after study intervention are in Section 8.3.5.

21. A POCBP is eligible to participate if they use a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or if they adhere to penile-vaginal intercourse abstinence as their preferred and usual lifestyle (abstinent on a long-term and persistent basis), as described in Appendix 5, during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention. The length of time required to continue contraception for each study intervention is:

MK-5684: 7 days

Fulvestrant: 365 days

Exemestane: 30 days

Observation only (ie, no study treatment): no contraception requirement per protocol, follow local institutional guidelines

Megestrol acetate: 11 days

Medroxyprogesterone acetate: 7 days

Alternating megestrol acetate and tamoxifen: 60 days

Letrozole: 21 days

Note: The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recent initiation) in relationship to the first dose of study intervention. Contraceptive use by POCBPs should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the local contraception requirements for any of the study interventions are more stringent than the requirements above, the local label requirements are to be followed. Medical history, menstrual history, and recent sexual activity should be reviewed by the investigator to decrease the risk for inclusion of a POCBP with an early undetected pregnancy. Abstains from breastfeeding during the study intervention period and for at least the length of time required for each study intervention after the last dose of study intervention:

◦ MK-5684: 7 days

◦ Fulvestrant: 200 days

◦ Exemestane: 7 days

◦ Observation only (ie, no study treatment): no breastfeeding requirement per protocol, follow local institutional guidelines

◦ Megestrol acetate: 11 days

◦ Medroxyprogesterone acetate: 7 days

◦ Alternating megestrol acetate and tamoxifen: 90 days (3 months following the last dose for lactation)

◦ Letrozole: 21 days

Medical history, menstrual history, and recent sexual activity have been reviewed by the investigator to decrease the risk for inclusion of a POCBP with an early undetected pregnancy.

Medical Conditions

1. Breast cancer amenable to treatment with curative intent.

2. Has advanced/metastatic, symptomatic visceral spread at risk of rapidly evolving into life-threatening complications, such as lymphangitic lung metastases, radiographic evidence of intratumoral cavitation or invasion/infiltration of a major blood vessel, bone marrow replacement, carcinomatous meningitis, significant symptomatic liver metastases, symptomatic pericardial effusion, symptomatic peritoneal carcinomatosis, or the need to achieve rapid symptom control. --08TSMW Participants with symptomatic pleural effusion who have dyspnea at rest requiring supplemental oxygen, but which is alleviated by drainage of the fluid can be enrolled. Participants with symptomatic ascitic effusion caused by peritoneal carcinomatosis which is alleviated after drainage of the ascitic fluid can be enrolled. Participants with symptomatic liver metastases include participants with rapidly increasing bilirubin >1.5 × ULN in the absence of biliary obstruction with involvement of over than 50% of liver parenchyma by the disease are excluded

3. Patients with only nonmeasurable lesions (eg, pleural effusion, ascites). Note: Skin only disease is excluded. Participants who have metastatic disease fulfilling the previous criteria in addition to skin disease may be enrolled. Note: Participants with bone-only disease can be included only if they have lytic or mixed lytic bone lesions with an identifiable soft tissue component which can be measured by RECIST 1.1 as evaluated by CT or MRI, and they are able to provide a biopsy either from the bone associated soft tissue (last archival or newly obtained), or from the locally advanced tissue (locally recurrent breast, chest wall, and/or regional lymph node and/or primary) if it coexists. Note: Chest wall recurrence can be used as a target lesion, only if measurable by diagnostic quality imaging modality (digital photography alone is not adequate).

4. Active, bleeding diathesis, or on oral anti-vitamin K medication (except low dose warfarin, LMWH and acetylsalicylic acid or equivalent, as long as the INR is ≤2.0).

5. Has a known germline BRCA mutation (deleterious or suspected deleterious) and has received previous treatment with PARP inhibition either in the adjuvant or metastatic setting or has a known BRCA mutation and PARP inhibitors are available and not medically contraindicated.

6. Has received any line of cytotoxic chemotherapy or PARPi in the inoperable or noncurative advanced/metastatic setting. a. Cytotoxic chemotherapy includes standard chemotherapy and ADCs, even if given concurrent to ET. b. Chemotherapy administered for less than 1 cycle will not be counted as a prior line of chemotherapy. c. There are no restrictions on prior use of approved CDK4/6 inhibitors, PI3K inhibitors, AKT inhibitors, or immunotherapy as these are not considered cytotoxic chemotherapy. d. Adjuvant and neoadjuvant chemotherapy are not considered as lines of excluded cytotoxic therapy in the noncurative setting.

7. Recurrence while on adjuvant CDK4/6 inhibitor and ET or within 24 months from last dose of the combination.

8. Has received elacestrant for a tumor with a known ESR1 mutation in a region where approved, available, and not medically contraindicated.

9. Has received both fulvestrant and exemestane in the metastatic setting.

10. Has nonepithelial cancers (germ cell tumors and sex cord-stromal tumors), borderline tumors (low malignant potential), mucinous, seromucinous that is predominantly mucinous, malignant Brenner’s tumor, low-grade serous, low-grade endometrioid, and undifferentiated carcinoma.

11. Has platinum-resistant ovarian cancer (defined as disease that has progressed per radiographic imaging within 180 days after the last dose of 1L platinum-based therapy) or platinum-refractory ovarian cancer (defined as disease that has progressed per radiographic imaging while receiving or within 28 days of the last dose of 1L platinumbased therapy).

12. Is a candidate for curative-intent surgery or curative-intent radiotherapy for ovarian cancer at the time of enrollment or during participation in the study.

13. Received more than 3 prior lines of systemic therapy for ovarian cancer.

14. Will receive treatment with bevacizumab for ovarian cancer.

15. Is ineligible for platinum doublet induction therapy in 3L.

16. High-grade (FIGO Grade 3 or poorly differentiated) endometroid carcinoma and nonendometrioid histologies of any type (including serous, clear cell, mixed, carcinosarcoma), and neuroendocrine tumors are not eligible. Uterine mesenchymal tumors such as an endometrial stromal sarcoma, leiomyosarcoma, or other types of pure sarcomas, and adenosarcomas are not eligible.

17. Has endometrial cancer of any histology that is either dMMR or POLE mutated. Note: Testing for POLE mutation is not required for this study; however, patients with known POLE mutations will not be eligible.

18. Tumor has aberrant p53 expression by IHC or a documented TP53 mutation.

19. Is a candidate for curative-intent surgery or curative-intent radiotherapy.

20. Has received more than 1 prior line of systemic anticancer therapy. Systemic anticancer therapy in the adjuvant/neoadjuvant setting will be counted as 1 line of therapy.

21. Has received prior nonplatinum-based systemic therapy (examples include but are not limited to single-agent chemotherapy, hormonal therapy, PARP inhibitors or other targeted therapy, ADCs, investigational agents or use of PD-1/PD-L1 inhibitors after progression on platinum-based chemotherapy).

22. Patient is receiving hormonal therapy for treatment of secondary malignancy (eg, adjuvant therapy for breast cancer).

23. Has confirmed or suspected adrenal metastases.

24. Known difficulty in tolerating oral medications, unable to swallow orally administered medication, or conditions which would impair absorption of oral medications such as uncontrolled nausea or vomiting (ie, CTCAE v5.0 ≥Grade 3 despite antiemetic therapy), ongoing gastrointestinal obstruction, motility disorder, malabsorption syndrome, or prior gastric bypass.

25. Has any prior history or current condition of adrenal insufficiency. Note: Participants with adrenal insufficiency-related AE due to prior systemic anticancer therapy that has recovered to ≤Grade 1 or baseline are eligible.

26. HIV-infected participants with a history of Kaposi’s sarcoma and/or Multicentric Castleman’s Disease.

27. Has presence of gastrointestinal condition (eg, malabsorption) that might affect the absorption of study medication.

28. History of pituitary dysfunction. Note: Exceptions may be considered after Sponsor consultation.

29. Poorly controlled diabetes mellitus.

30. Clinically significant abnormal serum potassium or sodium level.

31. Has any of the following at Screening Visit:Hypotension: systolic BP <110 mm Hg, orUncontrolled hypertension: systolic BP ≥160 mm Hg or diastolic BP ≥90 mm Hg, in 2 of 3 recordings with optimized antihypertensive therapy.

32. Active or unstable cardio/cerebro-vascular disease, including thromboembolic events and the following:History of stroke or transient ischemic attack within 6 months before the first dose of study intervention, history of myocardial infarction within 6 months before the first dose of study intervention, New York Heart Association Class III or IV cardiac disease or congestive heart failure, coronary heart disease that is symptomatic, or unstable angina.

33. History or family history of long QTc syndrome.

34. Has a resting ECG indicating uncontrolled, potentially reversible cardiac conditions as judged by the investigator (eg, unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation >470 msec, electrolyte disturbances, etc,) or has congenital long QT syndrome.

35. Has a history of seizure(s) within 6 months before providing documented informed consent or has any condition that may predispose to seizure within 12 months before the date of enrollment, including, but not limited to loss of consciousness or prior cerebrovascular accident, transient ischemic attack, or brain arteriovenous malformation; or intracranial masses such as a schwannoma or meningioma that is causing edema or mass effect.

36. Has a history of clinically significant ventricular arrhythmias (eg, ventricular tachycardia, ventricular fibrillation, torsades de pointes) or Mobitz II second degree or third-degree heart block without a permanent pacemaker in place.

37. Has known hypersensitivity to the components or excipients in: All Cohorts: MK-5684, fludrocortisone, or dexamethasone-- Cohort A: Fulvestrant or exemestane Cohort C: Megestrol acetate, medroxyprogesterone acetate, tamoxifen, or letrozole

38. Is unable to receive any of the study interventions or supportive medications used in their assigned cohort (ie, fulvestrant, exemestane, megestrol acetate, medroxyprogesterone acetate, tamoxifen, letrozole, fludrocortisone, dexamethasone, or MK-5684). For example, known bleeding disorder which, in the opinion of the investigator, would prohibit administration of fulvestrant.

39. Has received treatment with 5-α reductase inhibitors, estrogens (topical estrogens are allowed), progestogens (eg, postmenopausal hormone therapy), androgens, and/or cyproterone within 4 weeks before randomization.

40. Use of aldosterone antagonist (eg, spironolactone, eplerenone) and phenytoin within 4 weeks before the start of the study intervention.

41. Participants on an unstable dose of thyroid hormone therapy as judged by the investigator within 6 months before the start of the study intervention.

42. Has received colony-stimulating factors (eg, G-CSF, GM-CSF, or recombinant EPO) within 28 days before the date of randomization.

43. Systemic use of the following medications within 2 weeks before the first dose of study intervention:-- Strong CYP3A4 inducers: eg, avasimibe, carbamazepine, lumacaftor, phenobarbital, rifampicin, rifapentine, St John’s Wort (other strong CYP3A4 inducers that are not listed may be included and should be confirmed with the investigator) P-gp inhibitors: erythromycin, clarithromycin, rifampicin, ketoconazole, itraconazole, posaconazole, artesunate-pyronaridine, ritonavir, indinavir, nelfinavir, atazanavir, glecaprevir-pibrentasvir, simeprevir, ledipasvir-sofosbuvir, verapamil, diltiazem, dronedarone, propafenone, quinidine, cyclosporine, valspodar, milk thistle (Silybum marianum; other P-gp inhibitors that are not listed may be included and should be confirmed with the investigator)

44. Received prior systemic anticancer therapy within 4 weeks or 5 half-lives (whichever is shorter) and has not recovered to grade ≤ 1 or baseline from AE associated with anticancer therapy before randomization

45. Received prior radiotherapy within 2 weeks of start of study intervention, or has radiation-related toxicities, requiring corticosteroids. Note: Two weeks or fewer of palliative radiotherapy for non-CNS disease is permitted. The last palliative radiotherapy treatment must have been performed at least 7 days before the first dose of study intervention.

46. Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed. Refer to Section 6.5 for information on COVID-19 vaccines.

47. Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration.

48. Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study intervention.

49. Known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, low-risk early-stage prostate cancer (T1-T2a, Gleason score ≤6, and PSA <10 ng/mL) either treated with definitive intent or untreated in active surveillance with stable disease, or carcinoma in situ, excluding carcinoma in situ of the bladder, that have undergone potentially curative therapy are not excluded.

50. Known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, (ie, without evidence of progression) for at least 4 weeks as confirmed by repeat imaging performed during study screening, are clinically stable and have not required steroid treatment for at least 14 days before the first dose of study intervention.

51. Active infection requiring systemic therapy other than those permitted in Section 5.1.

52. History or current evidence of any condition, therapy, laboratory abnormality, or other circumstance that might confound the results of the study or interfere with the participant’s ability to cooperate with the requirements of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator.

53. History of stem cell/solid organ transplant.

54. Participants who have not adequately recovered from major surgery or have ongoing surgical complications.