A randomised trial of [18F]PSMA‐1007‐PET/CT versus NaF‐PET/CT for staging primary prostate cancer: A trial protocol

Abstract Background Prostate‐specific membrane antigen (PSMA)‐positron emission tomography/contrast‐enhanced computed tomography (PET/CT) is a sensitive imaging modality for prostate cancer (PCa). Due to lack of knowledge of the patient benefit, PSMA‐PET/CT is not yet recommended in the European guidelines for staging and treatment planning of patients with newly diagnosed PCa. We will investigate the potential difference in progression‐free survival (PFS) and quality of life (QoL) of using PSMA‐PET/CT versus sodium fluoride (NaF)‐PET/CT for staging and treatment planning in patients with newly diagnosed PCa. Study Design This is a prospective randomised controlled multicentre trial carried out at three centres in the Region of Southern Denmark. Endpoints The primary endpoint is PFS. Secondary endpoints are residual disease, stage migration, impact on treatment strategies, stage distribution, QoL and diagnostic accuracy measures. Patients and Methods Patients eligible for the study have newly diagnosed unfavourable intermediate‐ or high‐risk PCa. A total of 448 patients will be randomised 1:1 into two groups: (A) a control group staged with Na[18F]F‐PET/CT and (B) an intervention group staged with [18F]PSMA‐1007‐PET/CT. A subgroup in the intervention group will have a supplementary blinded Na[18F]F‐PET/CT performed for the purpose of performing accuracy analyses. QoL will be assessed at baseline and with regular intervals (3–12 months) during the study period. Treatment decisions are achieved at multidisciplinary team conferences based on the results of the respective scans and according to current Danish guidelines. Trial Registration The Regional Committees on Health Research Ethics for Southern Denmark (S‐20190161) and the Danish Medicines Agency (EudraCT Number 2021‐000123‐12) approved the study, and it has been registered on clinicaltrials.gov (Record 2020110469).

The 5-year relative survival rate approaches 100% for the vast majority (89%) of men diagnosed with PCa but drops to 30% for those diagnosed with stage IV disease. 2 For primary staging, current guidelines recommend traditional imaging, including bone scintigraphy (BS) and contrast-enhanced computed tomography (CECT). These are, however, rather inaccurate with reported sensitivities and specificities of 42%-80% and 82%, respectively. 3,4 BS reflects bone metabolism and may be replaced by the newer Na[ 18 F]F-positron emission tomography (PET) although this has not yet proven any added value. 5 The transmembrane protein, prostate-specific membrane antigen (PSMA), is expressed on the majority of PCa cells and has become a unique target for molecular imaging of PCa. PSMA ligands can be labelled with positron-emitting isotopes such as 18 F and 68 Ga for imaging. The 18 F isotope is beneficial regarding availability and production. PSMA-1007 is only sparsely excreted in the urinary tract, making diagnostics in the pelvic region favourable. 6 Accuracy studies of PSMA-PET/CT for lymph node staging in the primary setting have reported moderate sensitivities (59%) and high specificities (93%), but most studies have been performed with a 68 Ga-labelled tracer. 7,8 It has recently been shown in a randomised prospective trial that [ 68 Ga]Ga-PSMA-11 PET/CT had a 27% greater accuracy compared with conventional imaging with CECT and BS. Upstaging and management change were reported 22% and 13% more frequently for PSMA-PET/CT compared with conventional imaging, respectively. 9 Regarding the favourable [ 18 F]PSMA-1007-PET/CT, a multicentre retrospective study has shown promising sensitivity and specificity for lymph node staging of 85.9% and 99.5%, respectively. 10 The European guidelines report that it could be tempting to replace BS and CECT with PSMA-PET/CT in initial PCa staging, but the clinical benefit of detecting metastases at an earlier time point is still undetermined. Therefore, it is argued that results from randomised controlled trials (RCTs) evaluating the management and outcome should be available before a decision can be made to treat patients based on the results of these tests. 11 We are aware of neither previous studies, current studies nor studies being planned to evaluate the impact of replacing traditional imaging with up-to-date PSMA-PET/ CT on patient outcomes such as progression-free survival (PFS) and quality of life (QoL).
This study aims to provide knowledge of the role of PSMA-PET/ CT in the primary staging of PCa to improve evidence-based clinical decision-making.

| Objectives
The overall aim of this project is to investigate the impact on PFS and QoL of using [ 18

| Study design
This trial is a randomised controlled clinical trial following the Consolidated Standards of Reporting Trials (CONSORT) guidelines. 12 A total of 448 patients (power calculation is in the statistical section) will be included and randomised into a control group (A) and an intervention group (B) (Figure 1 and Appendix A). Patients in Group A will be staged by Na[ 18 F]F-PET/CT, that is, CECT for lymph node and soft tissue metastases, and Na[ 18 F]F-PET for bone metastases according to current practice at our centres. Patients in Group B will be staged by [ 18 Table 1. Patients will be recruited from the three urologic departments in the Region of Southern Denmark and referred for imaging prior to treatment in the clinical set-up. Scans will be performed in three nuclear medicine departments in the region.

| Enrolment and randomisation
Patient recruitment will be carried out in a collaborative effort by the regional departments of urology and nuclear medicine. Patients will receive oral and written study information, and acceptance to participate is documented in signed consent forms. Consenting patients will be randomised and allocated into one of the study groups. Randomisation will be performed 1:1 into Groups A and B with stratification according to risk status of high, unfavourable intermediate and low risk with suspected metastases, respectively. The randomisation will be executed in the REDCap database software (https://projectredcap.org/).  Table 2 for tracer specifications.

| Imaging techniques
The

| Reference standard
Metastatic disease will be deemed without further imaging or examinations if the presentation is considered of typical morphology and pattern for PCa, especially considering lymph nodes and bones. In other tissues, metastases will also be suspected by a typical appearance, and biopsy will be intended only as a part of the clinical set-up when possible and clinically relevant. Biopsies are not performed solely as a part of the study. Further imaging will be used as reference standard to confirm or exclude metastatic disease when clinically indicated (see Table 3).

| Clinical management
The patients will be discussed in a multidisciplinary team (MDT) conference based on the results of the scans and staging performed accordingly. If in doubt of metastases, further imaging or biopsy will be performed if possible and relevant. The MDT will suggest a treatment strategy that follows the contemporary national guidelines. 15 In a shared decision process with the patient, the final choice of treatment will be decided upon, and the patients may be treated by prostatectomy, radiotherapy, androgen deprivation therapy (ADT), chemotherapy or antiandrogens and, eventually, in combinations.

| QoL
QoL will be assessed using the following widely used questionnairesall of them were translated and cross-culturally validated in Danish: • Functional Assessment of Cancer Therapy-Prostate (FACT-P)-39 items 16 ; •

| PRIMARY AND SECONDARY ENDPOINTS
The primary endpoint, PFS, will be compared between Groups A and B and defined as the time from inclusion to progression (Appendix C) or death for any reason. Progression is defined as clinical or biochemical recurrence/progression. Progression can be con- prostatectomy and subsequent referral to salvage radiotherapy for completion of treatment will not be categorised as having progression but as having residual disease (Appendix D). Residual disease will be a secondary endpoint compared between the two groups too.
Progression is determined for patients undergoing palliative treatment with a subsequent confirmed rising PSA and/or progression on imaging, leading to initiation or change of treatment. 23 The distribution of disease stage and treatment strategy will be evaluated between the two groups as secondary endpoints. Overall survival is a secondary endpoint too and will be evaluated between Groups A and B after suitable time spans, expected after 5, 10, 15 and 20 years. Regarding QoL, changes from baseline to 12 months are of primary interest, and an 8-point decline in the global FACT-P score will be considered clinically relevant. We suggest that more sensitive and suggestively correct staging will lead to improved QoL, because the treatment initiated is expected to better fit each patient. For example, small metastases that might not be identified with Na[ 18 F]F-PET/CT can be taken into account and leave the patients with less unattended small metastatic lesions and hence avoiding initial curative intended treatment with possible side effects for patients with primary disseminated disease.

| Diagnostic accuracy and stage migration
The secondary endpoint of diagnostic accuracy and stage migration will be performed in a subgroup of patients within Group B where patients will act as their own controls. Hence, the comparison will be made for Na

| Statistical analysis plan and sample size determination
Descriptive statistics will be done according to data type: mean ± standard deviation or median (range) for symmetrically and asymmetrically distributed continuous variables, respectively, as judged visually with histograms including approximating normal curves; and frequencies and percentages for categorical variables. Continuous variables will be compared using a t test, and categorical variables using a chi-squared test. Additionally, regression analysis will be used to identify associations within data. Accuracy assessments of Na[ 18 F]F-PET/CT and [ 18 F]PSMA-1007-PET/CT will relate to sensitivity, specificity, positive and negative predictive values that will be judged upon the reference standard (Table 3)  This subgroup analysis will be made and published when the first 128 patients have been recruited in Group B. This interim analysis enables a potential early stopping due to futility, not due to early success. The primary hypothesis will not be tested in the interim analysis.

| DISCUSSION
Several studies have shown that PSMA-PET/CT is superior to BS and CECT for detecting relapse of PCa, and PSMA-PET/CT is introduced in the guidelines for this indication. 24,25 The first studies on PSMA-PET/CT for primary staging of PCa have been published, showing higher sensitivity to detecting metastases than BS and CECT. 26,27 PSMA-PET/CT is only cautiously introduced in the international guidelines for primary staging of intermediate-and high-risk PCa patients because of lack of evidence of whether the increased sensitivity will translate into patient benefit of being staged with this more sensitive modality. 11 Hofman et al. have performed a large randomised controlled study in a cross-over design. 9 They randomised the patients in two In this study, we hypothesise that staging patients with PSMA-PET/CT will lead to a longer PFS. Today, a significant group of PCa patients are diagnosed with residual disease after prostatectomy. 28,29 We believe that more sensitive imaging for primary staging will reduce this rate because of more correct initial staging and improved treatment for the individual patient, and ultimately a longer PFS, a longer overall survival, and improved QoL.
We expect stage migration in a group of patients staged with The recommendations for treatment have changed over the last decade 11 and with current opportunities, even localised treatment of a solitary metastasis may be considered relevant. 30 This means that using sensitive procedures for primary staging should be considered even more important than ever before.

Recurrence after prostatectomy
PSA rising from unmeasurable to above 0.2 ng/mL in two following measurements.

Recurrence after radiotherapy
PSA rising with 2 ng/mL above nadir in two following measurements.
Progression PSA rising in two following measurements AND/OR progression on imaging AND/OR clinical progression.

Castration resistance
Progression despite of castration.