Clonal Emergence and Regression During Radium-223 Therapy for Metastatic Prostate Cancer

This study proposes to document the presence of clonal emergence and regression during radium-223 therapy for metastatic prostate cancer by serial ctDNA analysis of tumor-associated mutations, using the clinically-available Guardant 360 platform. These data may provide important mechanistic insights into radium-223 therapy by 1) identifying mutations associated with radium-223 resistance or sensitivity, 2) providing new markers of treatment response in an individual, and 3) revealing antitumor effects from radium-223 that are not easily recognized with standard tumor response metrics. Positive finding based on this clinically-available platform will be readily applied by the oncology treatment community.

Inclusion criteria

• Prostate adenocarcinoma by history or medical records.
• Two or more bone metastases as demonstrated by imaging studies (technetium bone scan, fluoride PET scan, FDG PET scan, fluciclovine PET scan, CT scan, or MRI scan) or by biopsy.
• Patients must be on ADT with a GnRH receptor agonist/antagonist or orchiectomy, with or without an anti-androgen or testosterone synthesis inhibitor. Patients must have a documented castrate level of testosterone (<50ng/dL) and be willing to continue their GnRH agonist/antagonist during the course of radium-223 therapy.
• Patients may have had localized external beam radiation to as much as 20% of the skeleton
• Adequate hematopoietic, renal, and hepatic function. These parameters include:

• Hemoglobin ≥ 10gm/dL
• WBC ≥ 3.0K/mcL
• ANC ≥ 1.5K/mcL
• Platelet count ≥ 100K/mcL
• Creatinine < 1.5 ng/mL
• Total bilirubin <1.5 ng/mL.
• Albumin > 25 g/L
• Patients should have an elevated, relevant tumor marker such as PSA, CEA, or LDH.
• Age ≥18 years old
• Life expectancy of at least 24 weeks
• Subjects must be able to understand and be willing to sign the written informed consent form. A signed informed consent form must be appropriately obtained prior to the conduct of any trial-specific procedures. Subjects must be willing and able to comply with the protocol, including follow-up visits and examinations.
• Men of childbearing potential must agree to use adequate contraception beginning at the signing of the informed consent until at least 30 days after the last dose of radium-223 treatment or during the course of radium-223 treatment.
• Subjects must have had a Guardant 360 ctDNA-based genomic profile performed up to four months prior to the first dose of radium-223, with no new therapy started in the interim. This assay must show at least one single nucleotide variant, either missense or synonymous, or one amplification.
• Subjects should continue any previously-started bone-hardening agents (zoledronic acid or denosumab) during radium-223 therapy.
• All acute toxic effects of any prior treatment have resolved to NCI-CTCAE v 5.0 Grade 1 or less at the time of signing the Informed Consent Form (ICF).

Exclusion criteria

• Initiation of any additional anti-tumor therapy within 2 months of starting radium-223 treatment
• Presence of only lytic bone metastases
• Prior cytotoxic chemotherapy for metastatic PCa
• Prior systemic therapy with radionuclides (e.g., strontium-89, samarium-153, rhenium-186, or rhenium-188, or Radium Ra 223 dichloride) for the treatment of bony metastases
• Other malignancy requiring systemic therapy within the last 3 years (except non melanoma skin cancer or low-grade superficial bladder cancer)
• Visceral (i.e. liver, lung, brain, adrenal, brain, but not lymph node) metastases as assessed by chest, abdominal, or pelvic computed tomography, or other imaging modality)
• Lymphadenopathy exceeding 6 cm in short-axis diameter, or any size pelvic lymphadenopathy if it is thought to be a contributor to concurrent hydronephrosis
• Imminent spinal cord compression based on clinical findings and/or MRI. Treatment should be completed for spinal cord compression.
• Any infection ≥ Grade 2 per NCI-CTCAE version 5.0
• Cardiac failure NYHA III or IV
• Crohn's disease or ulcerative colitis
• Bone marrow dysplasia, myelodysplasia
• Fecal incontinence
• Inability to comply with the protocol and/or not willing or not available for follow-up assessments.
• Any condition which, in the investigator's opinion, makes the subject unsuitable for trial participation.
• Concurrent use of abiraterone or enzalutamide. A 28-day washout period is required for both agents.