This is a Phase 1b/2, open-label, multicenter platform trial to evaluate the antitumor activity and safety of etrumadenant (AB928)-based combination therapy in participants with metastatic castrate resistant prostate cancer (mCRPC).

General Inclusion Criteria:

• Male participants; age ≥ 18 years
• Metastatic castrate-resistant prostate cancer while on anti-androgen treatment with castrate levels of testosterone (≤1.7 nanomoles per liter [nmol/L] or 50 nanograms per deciliter [ng/dL])
• Measurable or non-measurable disease as per radiographic evaluation
• Participants with measurable disease may require a fresh tumor biopsy at study entry
• Eastern Cooperative Oncology Group (ECOG) Performance status of 0 or 1
• Life expectancy of at least 3 months
• Adequate hematologic and end-organ function
• Human immunodeficiency virus (HIV), Hepatitis B, and C test results negative prior to first study treatment

Inclusion Criteria for Participants receiving an enzalutamide-containing treatment

• Disease progression after prior treatment with abiraterone

Inclusion Criteria for Participants receiving a docetaxel-containing treatment

• Disease progression after prior androgen synthesis inhibitor therapy

Inclusion Criteria for all other Participants

• Disease progression after prior androgen synthesis inhibitor treatment and up to 2 prior lines of taxane chemotherapy

General Exclusion Criteria:

• Prior treatment with immune checkpoint blockade therapy
• Prior anticancer treatment including approved agents, systemic radiotherapy, or investigational therapy, within 2-4 weeks prior first study treatment
• Corrected QT interval (QTc) ≥480 msec using Fredericia's QT correction formula (based on an average of triplicate recordings)
• Prior allogeneic stem cell or solid organ transplantation
• Prior treatment with drugs that stimulate the immune system within 4 weeks prior to first study treatment
• Prior treatment with drugs that suppress the immune system within 2 weeks prior to first study treatment
• Received a live, attenuated vaccine within 4 weeks prior to first study treatment, or may need to receive a vaccine during study treatment
• Presence of metastases in the brain or cancer spreading into the cerebrospinal fluid - CSF (leptomeningeal disease)
• Prior pulmonary fibrosis, pneumonia, or pneumonitis
• Cancer other than prostate within 2 years prior to study entry, except for some cancers with a low risk of spreading like non-melanoma skin
• Prior treatment with an agent targeting the adenosine pathway
• No oral or IV antibiotics within 2 weeks prior to first study treatment
• No severe infection within 4 weeks prior to first study treatment
• No clinically significant cardiac disease
• Inability to swallow medications

Exclusion Criteria for Participants receiving an enzalutamide-containing treatment

• Prior treatment with docetaxel, cabazitaxel, or other taxane chemotherapy (prior docetaxel [up to 6 cycles] for hormone-sensitive prostate cancer is allowed if the last dose was at least 6 months prior to study treatment initiation)
• Prior treatment with enzalutamide or similar therapy other than abiraterone
• Active or history of autoimmune disease or immune deficiency
• History of severe allergic reactions to antibody therapy
• Concomitant use of a medication prohibited by the protocol (including certain transporter substrates as well as known strong CYP3A4 inducers and CYP3A4 inhibitors) within 4 weeks prior to and throughout study treatment

Exclusion Criteria for Participants receiving a docetaxel-containing treatment

• Prior treatment with docetaxel, cabazitaxel, or other taxane chemotherapy
• Active or history of autoimmune disease or immune deficiency
• History of severe allergic reactions to antibody therapy
• Concomitant use of a medication prohibited by the protocol (including certain transporter substrates as well as known strong CYP3A4 inducers and CYP3A4 inhibitors) within 4 weeks prior to and throughout study treatment

Exclusion Criteria for all other Participants

• Prior treatment with docetaxel, cabazitaxel, topoisomerase 1 inhibitors, or other taxane chemotherapy
• Active or history of autoimmune disease or immune deficiency
• History of severe allergic reactions to antibody therapy
• Concomitant use of a medication prohibited by the protocol (including certain transporter substrates as well as known strong CYP3A4 inducers and CYP3A4 inhibitors) within 4 weeks prior to and throughout study treatment

Arcus will provide access to individual de-identified participant data and related study documents (e.g., protocol, Statistical Analysis Plan [SAP], Clinical Study Report [CSR]) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions.

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