Received any radiopharmaceutical or radioligand therapy (eg, Radium-223, Strontium-89, Samarium-153, any [Lu-177]-compounds, any [Ac-225]-compounds, any [Pb-212 compounds). For participants with mCRPC, prior 177Lu-PSMA-617 is permitted
Received any prior hemi-body or whole-body radiotherapy, or prior external beam radiation therapy (EBRT) to greater than 25% of the bone marrow
Has a history of or ongoing acute pancreatitis within 1 year of screening
Has evidence of ongoing and untreated urinary tract obstruction (ie, hydronephrosis or hydroureter) or unmanageable urinary incontinence
Phase 1a (Cohort A1) only: Currently receiving neprilysin (NEP) inhibitors (ie, Entreso, racecadotril) and for whom images for dosimetry assessments cannot be acquired
Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Individuals with previously treated CNS metastases may participate provided:
- Any prior CNS-directed therapy is completed, including radiation or surgery, ≥14 days prior to the first dose of study intervention
- CNS disease is neurologically and radiologically stable, defined as without evidence of progression for ≥14 days by repeat imaging obtained prior to the first dose of study intervention
- Individuals receiving glucocorticoid therapy must not receive >10 mg prednisone daily or equivalent
- Individuals receiving prophylactic anticonvulsants must be on a stable dose for ≥14 days prior to the first dose of study intervention. Enzyme inducing anti-epileptic drugs for CNS metastases must be discontinued for at least 5 half-lives prior to the first dose of study intervention
Has any unresolved toxicities from prior therapy greater than National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (Version 5.0) Grade 1 at the time of starting trial treatment except for alopecia and peripheral neuropathy
Has significant cardiovascular disease
- Unstable angina or acute coronary syndrome within the past 2 months
- History of myocardial infarction within 6 months prior to planned start of trial treatment
- Documented left ventricular ejection fraction (LVEF) by any method of ≤40% in the 12 months prior to planned start of trial treatment, unless subsequent measurements (≥2 of any kind, separated by a minimum of 3 weeks) document LVEF recovery to >40%
- Grade ≥3 New York Heart Association functional classification system of heart failure, uncontrolled or symptomatic arrhythmias
Has prolongation of the corrected QTcF >470 msec during screening
Has active uncontrolled systemic bacterial, viral, fungal, or parasitic infection (except for fungal nail infection), or other clinically significant active disease process which, in the opinion of the investigator and the sponsor, makes it undesirable for the individual to participate in the trial. Screening for chronic conditions is not required
Has known active hepatitis B virus (HBV) (screening for HBV is not required for individuals who do not have a history of HBV, unless required by local regulations). Individuals with treated/chronic HBV are eligible for the trial provided they meet the following criteria:
- Individuals with positive hepatitis B surface antigen (HBsAg) must be on permitted suppressive antiviral therapy prior to Cycle 1 Day 1 (C1D1), remain on the same antiviral treatment throughout trial, and should follow local standards for continuation of therapy after completion of trial therapy
- Undetectable HBV DNA ≤28 days of C1D1
Has known active hepatitis C virus (HCV) (screening for HCV is not required for individuals who do not have a history of HCV unless required by local regulations). Individuals previously treated for HCV are eligible for the trial provided they meet the following criteria:
- Completion of curative antiviral therapy
- HCV viral load below the limit of quantification ≤28 days of C1D1
- Negative hepatitis C antibody result OR, if positive, then must be hepatitis C RNA negative
Has known untreated human immunodeficiency virus (HIV) infection (screening for HIV is not required unless required by local regulations). Participants on permitted antiretroviral therapy (ART) and who have well-controlled HIV infection/disease are eligible provided they meet the following criteria:
- Must be on a stable and permitted ART regimen without changes in drug or dose, for at least 4 weeks prior to C1D1 and have a viral load of <400 copies per mL prior to ≤28 days of C1D1
- Cluster of differentiation 4 positive (CD4+) T-cell count ≥350 cells/uL ≤28 days of C1D1
Has an active second malignancy unless in remission with life expectancy >2 years
Has received a vaccination with a live vaccine ≤7 days prior to enrollment
Is pregnant and/or planning to breastfeed during the trial or within 6 months of the last dose of trial intervention
Has known hypersensitivity to any component or excipient of LY4257496
Prior therapies:
- Bisphosphonates or RANK-L targeted agents (eg, denosumab) ≤7 days
- Cytotoxic therapies or targeted agents that are small molecule inhibitors ≤14 days or ≤5 half-lives, whichever is shorter
- Therapeutic monoclonal antibodies ≤28 days
- Radiotherapy
  - Palliative limited field radiation ≤7 days
- Major surgery ≤28 days