Lu-PSMA for Oligometastatic Prostate Cancer Treated With STereotactic Ablative Radiotherapy

Study Overview
=================
Brief Summary
-----------------
The aim of this study is to assess the progression free survival (PFS) of SABR alone and SABR + 177Lu-prostate-specific membrane antigen (PSMA) in patients with oligometastatic prostate cancer undergoing PSMA positron emission tomography (PET) staging.

Detailed Description
-----------------
Metastatic disease in patients involves treatment including systemic chemotherapy, hormonal therapy and androgen deprivation therapy. Oligometastases was termed to describe a state of metastatic transition wherein the cancer cells travel from the original site of tumour to other parts of the body and form fewer number of tumours. Sustained systemic therapies such as chemotherapy have been used as the Standard of care (SOC) in most cases. Novel radiotherapy like Lutetium-177 PSMA radionuclide therapy have been explored in earlier disease settings to further improve outcomes. Based on evidence from few previous trials and emerging safety data from ongoing trials, it is an effective addition to SOC to further improve patient outcomes. The detection of prostate cancer can be done by a highly sensitive and specific test using the PSMA-PET small molecules. The evidence of high uptake of these PSMA-PET small molecules assists in selection of patients potentially suitable for novel PSMA targeted radionuclide therapy. Previous studies have demonstrated novel molecular imaging techniques, particularly PSMA PET/CT in the biochemical recurrence setting is leading to an increasing number of patients being diagnosed with oligometastatic disease which would not have been detected using conventional imaging techniques. The Stereotactic ablative body radiotherapy (SABR) is also an emerging localised treatment option for oligometastatic prostate cancer. It delivers a highly focused beam of external radiation concentrated over a tumour and has been used to treat low volume metastatic disease to delay the use of systemic therapies. Results from previous studies show that it a safe, well-tolerated and progressively used in real-world clinical practice to treat patients with low volume of metastatic cancer. Based on the results of a previous trial done by this team, patients with one to three sites of disease treated with a single session of SABR showed promising outcomes. The aim of this trial is to evaluate the progression free survival of SABR alone and SABR + 177Lu-prostate-specific membrane antigen (PSMA) in patients with oligometastatic prostate cancer undergoing PSMA positron emission tomography (PET) staging. 92 men with oligometastatic prostate cancer will be enrolled in this trial and split into 1:1 ratio to either stereotactic ablative body radiotherapy (SABR) alone or SABR plus 2 cycles of 177Lu-PSMA over a period of 24 months.

Official Title
-----------------
Lu-PSMA for Oligometastatic Prostate Cancer Treated With STereotactic Ablative Radiotherapy, a Randomised Phase II Parallel Cohort Trial

Conditions
-----------------
Oligometastatic Prostate Cancer

Intervention / Treatment
-----------------
* Drug: 177Lu-PSMA


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male aged 18 years or older at screening Patient has provided written informed consent Histologically confirmed prostate adenocarcinoma w Prior definitive treatment of the primary with either curative intent radiotherapy and/or surgery Patient has 1-5 sites of nodal or bony metastases on 68Ga-PSMA or 18F-DCFPyL PET/CT with a score of 4 or 5 as defined by the E-PSMA criteria At least one site of disease with SUVmax twice the SUVmax of liver on PSMA PET (Ga-68 PSMA 11 or F-18 DCFPYL tracers only) Adequate haematological function as defined by: Absolute neutrophil count (ANC) ≥1.5 x 109/L Platelet count >150x 109/L Haemoglobin ≥100 g/L Creatinine Clearance ≥ 40mL/min (Cockcroft-Gault formula) Assessed as suitable for SABR by a radiation oncologist Patients must agree to use an adequate method of contraception Have a performance status of 0-1 on the ECOG Performance Scale Exclusion Criteria: Prior systemic therapy, radiation therapy, or surgery for metastatic prostate cancer. Prior ADT is allowed but ADT within 6 months of screening for the study is not allowed. If patients have received prior ADT, serum testosterone levels must be above the lower limit of normal No sites of PSMA negative metastatic disease evident on CT/bone scan Any visceral (AJCCC M1c) metastases Symptomatic cord compression, or clinical or imaging findings concerning for impending cord compression Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient's participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating Investigator Has a known additional malignancy that is progressing or required active treatment in the last 2 years Note: Basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer or carcinoma in situ such as breast cancer in situ that has undergone potentially curative therapy are not excluded.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Stereotactic ablative body radiotherapy (SABR) alone<br>1-3 fractions of SABR to all sites of disease | |
| Experimental: SABR plus 2 cycles of 177Lu-PSMA<br>cycles of 177Lu-PSMA with 1-3 fractions of SABR to all sites of disease between cycle 1 and 2 | Drug: 177Lu-PSMA<br>* Lutetium-177 (177Lu)-PSMA is a radiopharmaceutical comprised of a small molecule inhibitor of PSMA that binds with high affinity to PSMA, labelled with 177Lu. 177Lu has favourable characteristics for radionuclide therapy emitting both a short-range (1-2mm) cytotoxic beta-particle, minimising irradiation of non-targeted normal tissues, alongside gamma emission that allows imaging. Numerous retrospective series initially demonstrated high clinical activity and limited normal tissue toxicity using PSMA-617 and PSMA-I&T, which are the most advanced small molecule inhibitors of PSMA, radiolabelled with 177Lu<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the (bPFS) of SABR alone and SABR + 177Lu-PSMA | The biochemical progression free survival (bPFS) of SABR alone and SABR + 177Lu-prostate-specific membrane antigen (PSMA) in patients with oligometastatic prostate cancer undergoing PSMA positron emission tomography (PET) staging. | Through study completion, up until 12 months after the last patient commences treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The AEs according to CTCAE v5.0 | The type, grade and relationship to treatment of AEs will be assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v 5.0 | Through study completion, up until 4 months ± 10 days from the commencement of ADT following progression | 
| The PSA-response rate | PSA response will be defined as a 50% or greater decrease in PSA from baseline to the lowest post-baseline PSA result | Through study completion, up until time of biochemical progression +/- 10 days | 
| The ADT-free survival | ADT-FS is defined as the time from randomisation to the date of initiation of androgen deprivation therapy or date of death due to any cause | Through study completion, up until biochemical progression +/- 10 days | 
| The pattern of recurrence on PSMA PET | Pattern of relapse will be evaluated on the PSMA PET at progression in relation to baseline PSMA PET, including: a) number of new sites of disease; b) location of new disease of disease (pelvic nodes, extra-pelvic nodes, bone, viscera); c) progression at prior sites (yes or no) | Time of biochemical progression +/-10 days | 
| The patient reported quality of life | QoL will be assessed using the EORTC QLQC-30 and EQ-5D-5L questionnaires | From the date of randomisation to the date of progression | 
| The MDT PFS | MDT PFS is defined as the time from first MDT after initial treatment to first documented subsequent disease progression (biochemical, or clinical using the same definition as the primary endpoint) or date of death, whichever comes first. Only patients who received MDT as the only treatment modality after initial treatment will be included. | Time point after Cycle 2 (28 days follow up post Cycle 2) until biochemical progression | 
| The overall survival | OS is defined as the time from randomisation to the date of death from any cause | Time point post randomisation to the date of death from any cause | 
| Healthcare costs associated with delivering the intervention and management of AEs | Health economic analysis is planned to assess the real-world cost-effectiveness and broader economic impact of using 177Lu-PSMA + SABR compared to SABR alone (if an effect is observed). Costs included in the analysis will focus on those relevant to the intervention (177Lu-PSMA) including treatment-related hospitalisations, clinic visits, PSMA PET scans, and associated medical service utilisation. Additionally, healthcare resource used and their associated costs including those associated with the complications arising from each study arm will be extracted from hospital administrative records and data collected during the trial (e.g., CTCAE v 5.0 Toxicity Record) and compared to provide an understanding of overall costs. | Through study completion, an average of 3 years | 
| The PET-PFS | PET-PFS is defined as the time from randomisation to the date of radiological progression on PSMA PET/CT scan or death due to any cause, whichever comes first. Patients alive without a rise in PSA will be censored at last PSA assessment | Through study completion, from the date of randomisation to the date of radiological progression or death from any cause, whichever comes first. |