Assessing Efficacy of Neoadjuvant ADT in Localized High-Risk Prostate Cancer Patients Utilizing 18F-Flotufolastat PSMA PET/CT

This is a single-arm, phase II, open label study in patients with localized high- risk prostate cancer (LHRPC) treated with neoadjuvant ADT (leuprolide, degarelix, relugolix, or triptorelin) followed by radical prostatectomy (RP). This study aims to evaluate the efficacy of neoadjuvant ADT based on maximal standardized uptake value (SUVmax) changes on 18F-Flotufolastat prostate- specific membrane antigen (PSMA) PET/CT scan in patients with LHRPC. Additionally, it will investigate the prognostic value of SUVmax changes in predicting biochemical recurrence-free survival.

• Leuprolide (Drug), also known as Lupron, Eligard: 22.5 mg IM every 3 months × 2 doses
• Degarelix (Drug), also known as Firmagon: 240 mg SC loading dose, then 80 mg SC q28 days × 6 months
• Relugolix (Drug), also known as Orgovyx: 360 mg PO Day 1, then 120 mg PO daily × 6 months
• Triptorelin (Drug), also known as Trelstar: 11.25 mg IM every 3 months × 2 doses
• Bicalutamide (Drug), also known as Casodex: Given only with leuprolide or triptorelin; 50 mg PO daily for 30 days
• 18-F Flotufolastat PSMA PET (Diagnostic test), also known as Posluma: 296 MBq (8mCi) administered as an intravenous bolus injection prior to PSMA PET scan. May be administered diluted in normal saline (NS) or undiluted. The maximum volume of undiluted 18F-flotufolastat is 5mL. After administration, a flush with 0.9% NS will be given to ensure full delivery of the dose.
• Radical prostatectomy (Procedure): Surgery to occur 14 to 90 days after the pre-surgery visit. All RPs will be performed per institutional standard of care by fellowship-trained urologic oncologists, with an extended pelvic lymph-node dissection when clinically indicated.

Primary outcomes

• Objective response rate (ORR) based on PSMA PET [6 Months]: ORR is based on changes in maximum standard uptake value (SUVmax) on PSMA PET/CT imaging pre- and post-ADT. Complete response (CR) is defined as resolution of all PSMA-avid lesions. Partial response (PR) is defined as >30% decrease in SUVmax. Progressive disease (PD) is defined as >30% increase in SUVmax or presence of new PSMA-avid lesions. Stable disease (SD) is defined as not meeting criteria for CR, PR, or PD. ORR is defined as the proportion of participants having CR or PR after ADT based on SUVmax.
• ORR based on Response Evaluation Criteria in PSMA Imaging (RECIP 1.0) [6 Months]: ORR in this endpoint is based on RECIP 1.0 criteria. Complete response (CR) is defined as disappearance of all PSMA-avid disease. Partial response (PR) is defined as ≥30% increase in total tumor volume. Progressive disease (PD) is defined as ≥20% increase in total tumor volume or presence of new PSMA-avid lesions. Stable disease (SD) is defined as not meeting criteria for CR, PR, or PD. ORR is defined as the proportion of participants having CR or PR after ADT based on RECIP 1.0.

Secondary outcomes

• Prostate-Specific Antigen (PSA) response rate [36 Months]: Defined as the proportion of participants with a PSA reduction of at least 50% (PSA50) immediately prior to RP compared with baseline PSA after treatment with ADT.
• Biochemical recurrence-free survival (BCR) with testosterone recovery [36 months]: BCR with testosterone recovery is defined as the time from ADT initiation to PSA ≥0.2 ng/mL after RP once testosterone has normalized. Median times will be calculated for responders (CR and PR) and non-responders (SD and PD).

Sex: Male, ages: 18 Years to any

Inclusion Criteria:

* Signed informed consent must be obtained prior to participation in the study.
* Males aged ≥18 years.
* ECOG performance status ≤ 1
* Histologically confirmed adenocarcinoma of the prostate in a patient amenable to radical prostatectomy
* Pathologically proven prostate adenocarcinoma with ≥ 1 High-risk feature based on NCCN guidelines.

  1. cT3-cT4
  2. International Society of Urological Pathology (ISUP) Grade group 4 (Gleason score 8) or grade group 5 (Gleason score 9-10)
  3. PSA >20 ng/mL
* Clinically negative lymph nodes as established by PSMA PET/CT imaging. Patients who are node positive by PSMA PET/CT (e.g., N1), but whose nodes do not meet traditional size criteria for positivity (e.g., they measure ≥ 10mm on either the CT or MRI portion of the PET or on a dedicated CT or MRI) will not be considered N1 and would be eligible for this study.
* Patient is willing to use barrier-method of contraception along with another effective contraceptive method if engaged in sexual activity with a pregnant person or individual of childbearing potential (until 1 week after completing 18F-flotufolastat PSMA PET/CT Scans.
* Clinical laboratory values during screening:

  1. Hemoglobin ≥ 10.0 g/dL
  2. Absolute neutrophil count (ANC) ≥ 1.8 × 10⁹/L
  3. Platelets ≥ 100 × 10⁹/L

Exclusion Criteria:

* Known allergies, hypersensitivity, or intolerance to 18F-flotufolastat.
* Unable to receive androgen deprivation therapy.
* Prostate cancer with significant neuroendocrine or other rare variant pathology
* Evidence of metastatic disease involving bone, viscera, or lymph nodes superior to the bifurcation of the common iliac arteries on PSMA PET/CT
* Renal impairment (glomerular filtration rate <30 mL/min)
* History of prior radiation therapy for prostate cancer
* Any of the following within 6 months prior to the first dose of study treatment: severe or unstable angina, myocardial infarction, symptomatic congestive heart failure, clinically significant ventricular arrhythmias, or New York Heart Association Class II to IV heart disease.
* Uncontrolled severe hypertension, persistent uncontrolled diabetes, oxygen-dependent lung disease, chronic liver disease, or untreated HIV infection.
* Other malignancies other than prostate cancer in the past 5 years

  a. Cured basal cell or squamous cell skin cancers can be enrolled.
* Severe or uncontrolled concurrent infections are not eligible.
* Treated with concomitant cytotoxic cancer therapy for any other primary site.
* Patients who are unable to complete the study requirements of 2nd PSMA imaging or surgery for the primary endpoints.
* Any condition that, in the opinion of the investigator, would preclude participation in this study.

• Rohan Garje, M.D., Principal investigator, Miami Cancer Institute at Baptist Health, Inc.