A Study of GSK5458514 Administered Alone or In Combination With Other Anti-Cancer Agents in Participants With Prostate Cancer

Inclusion Criteria:

• Provide signed informed consent. Participants must be capable of providing informedconsent, which includes compliance with the requirements and restrictions listed inthe ICF and in this protocol.

• Male participants ≥18 years of age (or the legal age of consent in the jurisdictionin which the study is taking place) at the time of signing the ICF.

Male participants are eligible to participate if they agree to the following during the study intervention period and for at least 195 days, after the last dose of study intervention:

Refrain from donating sperm

PLUS either:

Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent.

OR

Must agree to use contraception as detailed below:

Agree to use a male condom and should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak when having sexual intercourse with a woman of childbearing potential (WOCBP) who is not currently pregnant.

• Participants with mCRPC:

• Histologically or cytologically confirmed adenocarcinoma of the prostate

• Metastatic disease diagnosed either by radiologic imaging (Positron emissiontomography [PET]- Computed tomography [CT]) and/or regular CT and/or Magneticresonance imaging (MRI) and/or bone scan

• Castration-resistant status as per PCWG3 criteria

• Has prior novel anti-androgen receptor therapy failure and had treatment failurewith 1-2 taxane-based chemotherapy regimens including for metastatic hormonesensitive prostate cancer.

• Has (1) at least 1 soft tissue target lesion per Prostate Cancer Working Group 3 (PCWG3)-modified Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) OR (2) if Non-Target soft tissue disease only per PCWG3-modified RECIST 1.1,may be included if a rise in PSA on 2 successive determinations at least 1 weekapart (the most recent screening measurement must have been ≥ 2 ng/mL) withtestosterone levels <50 ng/dL, OR (3) bone disease defined by PCWG3 (2 or morelesions on bone scan at screening), as determined by the investigator.

• Documented disease progression on most recent systemic therapy defined by fulfillingat least 1 of the PCWG3 criteria

• Have serum testosterone <50 ng/dL (<1.7 nM). Patients must have undergone bilateralorchiectomy or be on continuous androgen-deprivation therapy with a GnRH agonist orantagonist; this therapy must have been initiated at least 4 weeks prior torandomization and treatment must be continued throughout the study.

• Eastern Cooperative Oncology Group (ECOG) performance status ≤1, with nodeterioration in the 2 weeks before step-up treatment period Day 1.

• Have supplied tumor tissue from a newly obtained biopsy or archival tumor tissue forretrospective detection of Prostate-specific membrane antigen (PSMA) expression andother biomarker analysis. Tissue from a newly obtained biopsy is preferred. If anewly obtained biopsy is not feasible, archival tumor tissue preferably taken afterthe completion of the participant's last line of therapy prior to the first dose ofstudy drug is acceptable.

• Participants must have adequate organ function

Exclusion Criteria:

• Pathological finding consistent with small cell, neuroendocrine carcinoma of theprostate or any histology different from adenocarcinoma.

• History of central nervous system (CNS) metastases or leptomeningeal disease.

• Diagnosis of invasive malignancy or history of invasive malignancy other than thedisease under study within the last 5 years, except as noted below:

• History of an invasive malignancy for which the participant was definitivelytreated, and in which the participant has been disease free for at least 2years, and which, in the opinion of the principal investigator and medicalmonitor, is not expected to affect the evaluation of the effects of the studyintervention on the currently targeted disease under study

• Curatively treated basal cell carcinoma of the skin, superficial bladdercancer, squamous cell carcinoma of the skin, and/or in situ breast cancer maybe enrolled

• • Has ongoing adverse reaction(s) from prior therapy that have not recovered to ≤Grade 1 or to the baseline status preceding prior therapy, excluding [e.g.,alopecia, hearing loss, vitiligo, endocrinopathy managed with replacementtherapy, and Grade 2 neuropathy], or that the investigator, with the agreementof the sponsor, considers to be not clinically relevant for the tolerability ofstudy intervention in the current clinical study.

• Confirmed history or recurrent autoimmune disease that has required systemictreatments in the 2 years prior to screening. Participants with prior history ofautoimmune disease must be discussed with the medical monitor. Replacement therapyis not considered a form of systemic therapy (e.g., thyroid hormone for autoimmunethyroiditis or insulin is not exclusionary).

• Has evidence of interstitial lung disease, non-infectious pneumonitis, and/or ahistory of interstitial lung disease, non-infectious pneumonitis that requiredsteroid .

• Any anti-cancer therapy or prior systemic biologic therapy, including immunotherapywithin 4 weeks of start dose.

• Prior PSMA radionuclide therapy within 2 months prior to GSK5458514 unlessparticipant received <2 cycles.

• Prior PSMA-Chimeric antigen receptor T cell therapy (CAR-T) cell therapy and PSMA (Tcell engager) TCE/ Bispecific T cell engagers (BiTE) or other prostateTumor-associated antigens (TAA) specific T cell engager (TCE).

• Has any history of prior allogenic or autologous bone marrow transplant or othersolid organ transplant.

• Has known sensitivity to study intervention components or excipients or otherallergy that, in the opinion of the investigator or medical monitor, contraindicatesparticipation in the study.

• History of severe neurological or psychiatric disorder, including epilepsy,dementia, or major depression deemed to interfere with study assessments.

• Has had any major surgery (such as craniotomy, thoracotomy, or laparotomy, etc.)within 4 weeks prior to first dose of study intervention.

• Serious infections within 4 weeks prior to the first dose, including but not limitedto infectious complications, bacteremia, severe pneumonia treated with IVantibiotics for ≥2 weeks; active infections with therapeutic IV antibiotics within 2weeks prior to the first dose or oral antibiotics within 1 week prior to the firstdose. Participants who are receiving or have received prophylactic antibiotics (e.g., prophylaxis against urinary infections) are allowed.

Liver safety exclusion criteria:

• Has an Alanine aminotransferase (ALT) value >2.5x upper limit of normal (ULN) or >5xULN if documented history of liver metastases.

• Has a total bilirubin value >1.5x ULN.

• Has cirrhosis or current unstable liver or biliary disease per investigatorassessment defined by the presence of ascites, encephalopathy, coagulopathy,hypoalbuminemia, esophageal/gastric varices, or persistent jaundice.

• Has documented presence of Hepatitis B surface antigen (HBsAg), at screening orwithin 3 months prior to the first dose of study intervention.

• Has a positive Hepatitis C virus (HCV) antibody test result at screening or within 3months prior to Cycle 1 Day 1 unless the participant can meet the followingcriteria: NOTE: Participants with a positive HCV antibody test result due to priorresolved disease can be enrolled if a confirmatory negative HCV RNA test is obtainedand the participant otherwise meets entry criteria

• Has a positive HCV ribonucleic acid (RNA) test result at screening or within 3months prior to the first dose of study intervention. NOTE: The HCV RNA test isoptional, and participants with a negative HCV antibody test are not required toundergo HCV RNA testing as well.

• Is unable to adhere to the protocol defined SoA, including requirements for theFollow-up Period of the study, study procedures, restrictions, and requirements asdetermined by the investigator.