The main purpose of this study is to evaluate safety, tolerability, and efficacy of LY4257496 alone and as part of relevant standard of care (SOC) combination therapy in participants with Gastrin-releasing Peptide Receptor (GRPR)-positive advanced cancer, including but not limited to breast, colorectal, prostate, endometrial, esophageal, gastroesophageal (GE) junction, and gastric cancer. The study will also evaluate the safety, tolerability, and efficacy of LY4257529 to identify cancer with high levels of a protein called GRPR. This is a 2-part study. Participation could last up to 36 weeks or until your tumor progresses.

Inclusion Criteria:

• Must have histologically or cytologically proven diagnosis of locally advanced, unresectable, or metastatic cancer.

• Must be assessed by computed tomography (CT)/magnetic resonance imaging (MRI) to confirm at least 1 of the following:

  • At least 1 measurable target lesion per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
  • If only bone lesions are present without a soft-tissue component, a bone scan or MRI must confirm at least 2 detectable lesions considered to represent active metastases

• Must have GRPR-positive disease, defined by investigator assessment of GRPR imaging.

• Must have the following histologically or cytologically confirmed diagnosis:

  • Estrogen receptor (ER+)/human epidermal growth factor receptor 2 (HER2-) breast cancer
  • ER+/HER2+ breast cancer
  • Esophageal squamous cell carcinoma
  • Adenocarcinoma of the stomach, gastroesophageal junction, or esophagus
  • Colorectal carcinoma
  • Metastatic castration-resistant prostate cancer
  • Endometrial carcinoma. Carcinosarcoma is eligible. Uterine leiomyosarcoma, adenosarcoma, or endometrial stromal sarcoma is not eligible.
  • Low-grade papillary serous ovarian cancer
  • Other non-Central Nervous System (CNS) primary GRPR-positive solid tumors (Cohorts A1 dose escalation and D1 dose expansion only)

• For participants with breast cancer diagnosis, where possible, ER and HER2 status should be assessed from the most recent tissue biopsy taken at the time of presentation with recurrent or metastatic disease.

  • To fulfill the requirement for ER+ disease by local testing, a tumor must express the ER immunohistochemistry, as defined in the relevant American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines.
  • HER2 status should be determined by local testing, as defined in the relevant ASCO/CAP Guidelines.

• Must have an Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to 1.

• Must be able to comply with outpatient treatment, laboratory monitoring, imaging, and required clinic visits for the duration of trial participation.

Exclusion Criteria:

• Phase 1a (Cohort A1 and A2) only: Previously received radiopharmaceutical or radioligand therapy. For participants with prostate cancer, prior ¹⁷⁷Lu-prostate-specific membrane antigen (PSMA) is permitted.

• Has a history of ongoing acute pancreatitis within 1 year of screening.

• Previously received any prior hemi-body or whole-body radiotherapy, or prior external beam radiation therapy (EBRT) to greater than 25% of the bone marrow.

• A bone superscan, defined as a bone scan that demonstrates markedly increased skeletal radioisotope uptake relative to soft tissues in association with absent or faint genitourinary tract activity.

• Has evidence of ongoing and untreated urinary tract obstruction or unmanageable urinary incontinence.

• Have known active hepatitis B virus (HBV). Exception: Individuals with chronic HBV if they:

  • Have positive HBsAg
  • Are on suppressive antiviral therapy, as allowed per local regulations prior to C1D1
  • Remain on the same antiviral treatment throughout study, and should follow local standards for continuation of therapy after completion of trial therapy.
  • Have undetectable HBV DNA ≤14 days of C1D1.

• Have known active hepatitis C virus (HCV). Exception: Individuals previously treated for HCV if they:

  • Completed curative antiviral therapy.
  • Have an HCV viral load below the limit of quantification ≤14 days of C1D1 and.
  • Are positive for anti-HCV antibodies and negative for HCV ribonucleic acid (RNA) before randomization.

• Have untreated human immunodeficiency virus (HIV) infection. Exception: Individuals who have well-controlled HIV infection/disease and they:

  • Are on a stable and permitted antiretroviral therapy (ART) regimen without changes in drug or dose, for at least 4 weeks prior to C1D1
  • Have a viral load of <400 copies/mL ≤14 days of C1D1.
  • Have a CD4+ T-cell count ≥350 cells/mL ≤14 days of C1D1.
  • Have not had an opportunistic infection within the past 12 months.

• Has an active second malignancy unless in remission with life expectancy greater than 2 years.

• Has known hypersensitivity to any component or excipient of LY4257496.