A Study of Tarlatamab in Participants With Neuroendocrine Prostate Cancer

Open to males ages 18 years and up

(Part 1: Dose Exploration and Part 2: Dose Expansion):

- Participant has provided informed consent prior to initiation of any study specific activities/procedures. - Men aged ≥ 18 years at time of signing the informed consent. - Metastatic de novo or treatment-emergent neuroendocrine prostate cancer (NEPC) defined by histological, immunohistochemistry, or genomic analyses of baseline tumor tissue (by local assessment) or circulating tumor DNA (ctDNA) (by local assessment) as per protocol - At least 1 line of prior systemic treatment per protocol. - Participants with treatment-emergent NEPC or de novo NEPC with histologic evidence of prostate cancer with neuroendocrine differentiation without a history of bilateral orchiectomy are required to remain on luteinizing hormone-releasing hormone (LHRH) analogue therapy during the course of protocol therapy - Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 per Prostate Cancer Working Group 3 (PCWG3) modifications - Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2 - Participants with treated brain metastases are eligible provided they meet defined criteria - Adequate organ function as defined in protocol Inclusion Criteria (Part 2: Biomarker Expansion): Participants are eligible to be included in Part 2: Biomarker Expansion of the study only if all of the following criteria apply: - Participants aged ≥ 18 years at time of signing the informed consent. - Metastatic de novo or treatment-emergent NEPC not amenable to curative treatment with the following characteristics: - Neuroendocrine prostate carcinoma defined as either poorly differentiated carcinoma with similar histology as small cell lung cancer (SCLC), mixed tumors with both prostate adenocarcinoma and small cell morphologies, or cancers with high clinical or pathological suspicion for NEPC. - Tumor must be positive for DLL3 expression according to central pathology review. - Progressed on at least 1 line of prior systemic treatment with a platinum containing agent - Exception: participants may also be included if the aforementioned therapeutic options were medically not appropriate for them. In these cases, the reason(s) why required prior therapies were medically not appropriate should be documented in the participant's electronic case report form (eCRF). - Measurable disease per RECIST 1.1 per PCWG3 modifications - Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2 - Minimum life expectancy of 12 weeks, in the opinion of the investigator - Participants with treated brain metastases are eligible provided they meet the following criteria: - Definitive treatment was completed at least 2 weeks prior to the first planned dose of study treatment (stereotactic radiosurgery at least 7 days prior to first planned dose of study treatment) - At least 7 days prior to treatment: any central nervous system (CNS) disease is clinically stable, participant is off steroids for CNS disease (unless steroids are indicated for a reason unrelated to CNS disease), and participant is off or on stable doses of anti-epileptic drugs.

(Part 1: Dose Exploration, Part 2: Dose Expansion and Part 2: Biomarker

Expansion ): - History of other malignancy within the past 2 years, with exceptions: - Malignancy treated with curative intent and with no known active disease present for ≥ 2 years before enrollment and felt to be at low risk for recurrence by the treating physician - Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease. - Adequately treated non-muscle invasive urothelial carcinoma - History or presence of hematological malignancies unless curatively treated with no evidence of disease ≥ 2 years - Untreated or symptomatic brain metastases and leptomeningeal disease - Anti-tumor therapy within 28 days of study day 1; concurrent use of hormone deprivation therapy for hormone refractory prostate is permitted; participants on a stable bisphosphonate or denosumab prior to study day 1 are eligible Exceptions: - Participants who received conventional chemotherapy are eligible if at least 14 days have elapsed and if all treatment-related toxicities have resolved to Grade ≤ 1 - Prior palliative radiotherapy must have been completed at least 7 days before the first dose of Tarlatamab - Participants who received androgen signaling inhibitor are eligible if at least 14 days have elapsed and if all treatment-related toxicity has been resolved to Grade ≤ 1 - Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior study day 1 - Active autoimmune disease requiring systemic treatment within the past 12 months - Known positive test for human immunodeficiency virus (HIV) or hepatitis - Unresolved toxicities from prior anti-tumor therapy, defined as not having resolved to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 grade 0 or 1 (with the exception of alopecia or toxicities that are stable and well-controlled) - History of hypophysitis or pituitary dysfunction - Has evidence of interstitial lung disease or active, non-infectious pneumonitis. - Participants on prior delta-like protein 3 (DLL3)-targeted therapy may be eligible if discussed with Amgen medical monitor prior to enrollment - Evidence of severe acute respiratory syndrome coronavirus 2 (SARS-COV2) infection unless agreed upon with Medical Monitor and with no acute symptoms of coronavirus disease 2019 (COVID19) disease within 14 days prior to first dose of investigational product (counted from day of positive test for asymptomatic participants).