Measuring Circulating Tumor Deoxyribonucleic Acid Tumor Fraction to Guide Early 177Lu-PSMA-617 Treatment Discontinuation in Patients With Metastatic Castration-Resistant Prostate Cancer, DYNAMO Trial

OUTLINE:

CYCLES 1 AND 2: Patients receive 177Lu-PSMA-617 intravenously (IV) over 20-30 minutes on day 1 of each cycle. Cycles repeat every 6 weeks for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection with ctDNA TF testing at baseline and C2D1. Patients with undetectable ctDNA TF (< 3%) on C2D1 continue to receive 177Lu-PSMA-617 as above in the absence of disease progression or unacceptable toxicity. Patients with detectable ctDNA TF (≥ 3%) on C2D1 are randomized to 1 of 2 arms.

CYCLE 3+ ARM I: Starting with cycle 3, patients receive 177Lu-PSMA-617 IV over 20-30 minutes on day 1 of each cycle. Cycles repeat every 6 weeks in the absence of disease progression or unacceptable toxicity.

CYCLE 3+ ARM II: Starting with cycle 3, patients receive docetaxel IV on day 1 of each cycle. Cycles repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.

Additionally, all patients undergo PSMA positron emission tomography (PET) during screening, single photon emission computed tomography (SPECT)/computed tomography (CT) on study, and additional blood sample collection as well as CT throughout the study.

After completion of study treatment, patients are followed up every 12 weeks for up to 1 year.

• Lutetium Lu 177 Vipivotide Tetraxetan (Drug), also known as 177Lu-labeled PSMA-617, 177Lu-PSMA-617, Pluvicto, AAA 617, AAA-617, AAA617, Lu177-PSMA-617, Lutetium Lu 177-PSMA-617, Lutetium-177-PSMA-617: Given IV
• Cell-free Circulating Tumor DNA Assay (Procedure), also known as ctDNA Assay, Signatera: Undergo ctDNA TF testing
• Computed Tomography (Procedure), also known as CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, Diagnostic CAT Scan, Diagnostic CAT Scan Service Type, tomography: Undergo CT
• Docetaxel (Drug), also known as Docecad, RP 56976, RP-56976, RP56976, Taxotere, Taxotere Injection Concentrate: Given IV
• PSMA PET Scan (Procedure), also known as Prostate-specific Membrane Antigen PET, PSMA PET, PSMA-Positron emission tomography: Undergo PSMA PET
• Single Photon Tomography and Computed Tomography Scan (Procedure), also known as SPECT/CT, SPECT/CT SCAN: Undergo SPECT/CT
• Biospecimen Collection (Procedure), also known as Biological Sample Collection, Biospecimen Collected, Sample Collection, Specimen Collection: Undergo blood sample collection

Primary outcomes

• Number and proportion among those recruited with detectable circulating tumor deoxyribonucleic acid (ctDNA) tumor fraction who undergo randomization [Up to 2 cycles (Cycle length = 6 weeks)]: Will be analyzed descriptively. Among patients who initiate lutetium Lu 177 vipivotide tetraxetan and undergo cycle (C) 2 day (D) 1 ctDNA tumor fraction assessment, the number (and proportion among those recruited) with detectable ctDNA tumor fraction who undergo randomization will be reported with a two-sided 95% Wilson confidence interval.
• Number of patients screened, enrolled, evaluable for C2D1 ctDNA tumor fraction and for who cycle 3 is administered [Up to cycle 3 administration (Cycle length = 6 weeks)]: Will report the number of patients screened, enrolled, evaluable for C2D1 (week 13) ctDNA tumor fraction, classified as having detectable versus undetectable ctDNA tumor fraction, and for who cycle 3 is administered. Reasons for failure to undergo C1D28 ctDNA assessment or randomization will be tabulated.

Secondary outcomes

• Radiographic progression free survival (PFS) [From randomization to disease progression, clinical progression, or death, whichever occurs first, assessed up to 1 year]: Will be estimated in the subset of patients who undergo randomization. Disease progression assessed per modified Response Evaluation Criteria in Solid Tumors criteria or the Prostate Cancer Working Group 3 criteria for bone lesions. Clinical progression as determined by the treating physician. Will be estimated using the Kaplan-Meier method. Differences between groups will be evaluated using the log-rank test and the hazard ratio from a Cox regression model with treatment group as the predictor variable following assessment of proportional hazards. Will also visualize PFS point estimates and 95% confidence interval (CI) bands over time and report median and 95% CIs of PFS for each group.
• Overall survival [From the start of treatment until death from any cause, assessed up to 1 year]: Will be estimated in the subset of patients who undergo randomization. Will be estimated using the Kaplan-Meier method. Differences between groups will be evaluated using the log-rank test and the hazard ratio from a Cox regression model with treatment group as the predictor variable following assessment of proportional hazards.
• Prostate-specific antigen (PSA) PFS [From the start of treatment until PSA progression, assessed up to 1 year]: Will be estimated in the subset of patients who undergo randomization. Will be estimated using the Kaplan-Meier method. Differences between groups will be evaluated using the log-rank test and the hazard ratio from a Cox regression model with treatment group as the predictor variable following assessment of proportional hazards.
• Proportion of patients with a ≥ 50% decline in PSA from baseline (PSA50) response rate [Up to 1 year]: Will be estimated in the subset of patients who undergo randomization. Will be reported as a percentage with 95% CI calculated using Wilson's method. Changes in PSA from baseline, with patients achieving PSA50, may be visualized using waterfall plots.
• Duration of response [From the time measurement criteria are met for complete response or partial response (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 1 year]: Will be estimated in the subset of patients who undergo randomization.

Sex: Male, ages: 18 Years to any

Inclusion Criteria:

* Willing and able to provide informed consent
* Adult males ≥ 18 years age
* History of histologically confirmed adenocarcinoma of the prostate without evidence of neuroendocrine or small cell differentiation. If histology is not available, patients must have metastatic disease typical of prostate cancer (i.e., involving bone or pelvic lymph nodes or para-aortic lymph nodes)
* Evidence of metastatic disease on bone scan or CT scan
* Patient must have evidence of castration- resistant prostate cancer as evidenced by PSA progression (per Prostate Cancer Working Group 3 \[PCWG3\] criteria) and a castrate serum testosterone level (i.e., ≤ 50 mg/dL)

  * Serum/plasma PSA progression defined as 2 consecutive increases in PSA over a previous reference value measured at least 1 week prior. The minimal start value is 2.0 ng/mL
* Eastern Cooperative Oncology Group (ECOG) performance status 0-2
* Prior treatment and progression on at least one androgen receptor pathway inhibitor (ARPI), in either castration-sensitive or castration-resistant setting
* Eligible for treatment with either 177Lu-PSMA-617 or docetaxel as per their respective Food and Drug Administration (FDA) labels
* Absolute neutrophil count ≥ 1.5 x 10\^9/L
* Platelet count ≥ 100 x 10\^9/L
* Hemoglobin ≥ 9 g/dL
* Creatinine clearance ≥ 50 ml/min (calculated by Cockcroft-Gault formula)
* Total bilirubin ≤ 1.5 x upper limit of normal (ULN) except for patients with known Gilbert's syndrome (direct bilirubin ≤ 1.5 x ULN)
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN, unless liver metastases are present in which case they must be ≤ 5 x ULN. For patients with known Gilbert's Syndrome they must be ≤ 3 x ULN
* Able to comply with study requirements including provision of peripheral blood samples at specified time points for correlative studies

Exclusion Criteria:

* Evidence of serious and/or unstable pre-existing medical, psychiatric or other condition that could interfere with patient safety or provision of informed consent to participate in this study
* Evidence of metastatic neuroendocrine/small cell prostate cancer (NEPC). Note: baseline biopsy is not required
* Patients receiving any systemic therapy (aside from a luteinizing hormone-releasing hormone \[LHRH\] analogue) or radiotherapy within 2 weeks prior to study treatment
* Persistent toxicities (CTCAE grade > 2) from prior cancer therapy, excluding alopecia and stable neuropathy
* Patients considered a poor medical risk due to a serious, uncontrolled medical disorder or active, uncontrolled infection. Examples include, but are not limited to uncontrolled seizure disorder, unstable spinal cord compression, superior vena cava syndrome, or any psychiatric disorder that prohibits obtaining informed consent
* Patients who are known to be serologically positive for human immunodeficiency virus (HIV) and a CD4 count < 200
* Patients with known active hepatitis (i.e. hepatitis B or C). Prior hepatitis C infection is allowed as long as polymerase chain reaction (PCR) is negative
* Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery
* Serious cardiac disorder, including but not limited to uncontrolled ventricular arrhythmia, recent (within 12 months) myocardial infarction, resting electrocardiogram (ECG) indicating Fridericia's corrected QT interval prolongation > 500ms, or congenital long QT syndrome
* Prior systemic chemotherapy with taxane chemotherapy, including in hormone sensitive setting (e.g. docetaxel or cabazitaxel)
* Brain metastases or active epidural disease (treated epidural disease is permitted)

  * Note: baseline brain imaging is not required
* Contraindication to prednisone therapy including poorly controlled diabetes mellitus

• Michael Schweizer, MD, Principal investigator, Fred Hutch/University of Washington Cancer Consortium