The purpose of this study is to assess the safety and tolerability, describe the dose-limiting toxicities (DLTs), and determine the maximum tolerated dose (MTD) or maximum administered dose (MAD [in the absence of establishing the MTD]) for single agent MEDI3726 in subjects with mCRPC who have received prior treatment with abiraterone or enzalutamide, with or without a prior taxane-based chemotherapy in the mCRPC setting.

Inclusion Criteria:

• Age ≥ 18 years at the time of screening.

• Histologically confirmed diagnosis of metastatic castration-resistant prostate adenocarcinoma (mCRPC).

• Documented PD in subjects with mCRPC as assessed by the Investigator and defined by at least one of the following according to the PCWG3 criteria:

  1. Radiographic progression.
  2. PSA progression.

• Prior exposure to abiraterone or enzalutamide of at least 12 weeks in the mCRPC setting.

NOTE: Subjects who have received both abiraterone and enzalutamide in the mCRPC setting are eligible.

• In dose escalation: Prior taxane-based chemotherapy in the mCRPC setting is:

  1. Required for Arm A.

  2. Excluded for Arm B.

  3. Optional for Arm C.

     Exclusion Criteria:

• Subjects with neuroendocrine, neuroendocrine differentiation and/or small cell prostate cancer.

• The subject has received any conventional or investigational anti-cancer treatment within 21 days before the first dose of investigational product, with the following modifications:

  1. At least 14 days before the first dose of investigational product since completion of treatment with abiraterone or enzalutamide
  2. At least 14 days before the first dose of investigational product since completion of prior taxane-based chemotherapy
  3. At least 28 days before the first dose of investigational product since completion of treatment with Radium-223.
  4. At least 42 days before the first dose of investigational product since completion of prior bicalutamide and nilutamide treatment.

NOTE: An LHRH agonist or antagonist required for ongoing testosterone suppression will be permitted if Inclusion Criterion is satisfied.

• Prior exposure to PSMA-directed therapies.

• Subjects with previous radiotherapy for the treatment of unresectable, locally advanced or metastatic prostate cancer are excluded if:

  1. More than 25% of marrow-bearing bone has been irradiated.
  2. The last fraction of radiotherapy has been administered within approximately 2 weeks prior to the first dose of investigational product.

• Brain metastases that are untreated, symptomatic, or require therapy to control symptoms; or any radiation, surgery, or other therapy to control symptoms from brain metastases within 2 months prior to the first dose of investigational product.

• Subjects with known history of peripheral vasculopathies including, but not limited to, macro and microangiopathies secondary to diabetes, peripheral arteriopathy of any cause, intermittent claudication, repeated and/or non-healing ulcers of any cause.