This study is centrally approved by the Quebec Multicentric Ethics Committee at the sponsor site (CHUM – approval number MP-02-2021-9258). The trial is funded by the Canadian Cancer Society with in-kind radiotracer provided in part by Lantheus Medical.
Objective
To determine if PSMA PET/CT guided intensification of therapy is superior to therapy based on conventional imaging as measured by improved failure free survival and other cancer control outcomes, and whether it is associated with differences in rates of toxicity or quality of life.
Study design
This is a prospective randomized, multi-centre, phase III superiority trial comparing PSMA PET/CT guided intensification of therapy vs. conventional imaging guided therapy in patients with high risk PCa, on the basis of UCSF’s Cancer of the Prostate Risk Assessment (CAPRA) score [20] or clinical node positive by conventional staging, who are being offered primary RT or RP or men with BF post RP who are being offered salvage RT (Fig. 1).
Patient randomization will be stratified according to:
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1.
Therapeutic cohort (high-risk RT, high-risk RP, salvage RT post RP)
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2.
Planned use of pelvic lymph node radiotherapy (PLNRT) among patients receiving RT
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3.
Planned use of hormone therapy (HT) in the patient’s conventional imaging guided treatment plan.
Patients will be randomized 1:1 to receive PSMA PET/CT by variable block randomization through CASTOR’s Electronic Data Capture (EDC) system. Participants will be enrolled by study personnel at each participating institution and assigned to study arm per randomization. This is an intent-to-treat analysis and all randomized at-risk patients will be included in the primary analysis. A significance level of 0.05 will be used to determine significance in all analyses.
Study endpoints
Primary endpoint:
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Failure-free survival, defined as time to BF, local/regional failure (pathology or conventional imaging), distant metastasis (conventional imaging), or death from any cause.
Secondary endpoints:
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Adverse events (AE), as measured by the Common Terminology Criteria for Adverse Events (CTCAE) v.5
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Biochemical failure (BF)
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Local failure or regional failure on conventional imaging
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Distant metastasis on conventional imaging
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Prostate Cancer Specific Survival
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Overall Survival (OS)
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Time to subsequent next-line therapy
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Health-related quality of life (HRQoL), as measured by Expanded Prostate Cancer Index Composite 26 (EPIC-26) and EORTC Core Quality of Life Questionnaire (QLQ-C30)
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Detection yield: proportion of patients where PSMA PET/CT identifies a previously undetected lesion.
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Rate and nature of treatment intensification.
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Cost effectiveness: incremental cost per Quality-Adjusted Life Years (QALY) gained
Patient selection
Inclusion criteria
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Histological diagnosis of adenocarcinoma of the prostate planned for curative-intent standard-of-care RT (primary or salvage post RP) or RP with lymph node dissection.
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Age ≥ 18
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High risk of regional or distant metastases as defined by any of:
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° Newly diagnosed and untreated PCa with CAPRA score 6–10, or stage cN1.
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° Prior history of RP and BF (PSA > 0.1 ng/mL).
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Patients must provide study-specific informed consent prior to study entry.
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Eastern Cooperative Oncology Group (ECOG) performance status ≤2
Exclusion criteria
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Active or prior androgen deprivation therapy (except 5-alpha reductase inhibitor) terminated < 12 months prior to enrollment.
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Prior or planned PSMA PET/CT scan outside of this clinical trial.
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Charlson Comorbidity Index > 5 (see Appendix 2).
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Prior curative intent treatment for PCa with local therapy other than surgery (primary RT or ablative therapies)
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Evidence of extra-pelvic nodal disease (M1a) on conventional imaging (if performed)
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Evidence of metastatic disease (M1b bone, M1c viscera/soft tissue) on conventional imaging (if performed)
Pre-treatment evaluation
Within 120 days prior to randomization:
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History and targeted physical examination (as needed), including prior cancer therapies
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Charlson comorbidity index
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Performance status
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Conventional imaging guided treatment plan documented
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PSA (within 60 days)
Randomization
Prior to treatment (RT or surgery)
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EPIC-26, QLQ-C30, and EQ-5D-5L questionnaires
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Adverse event evaluation, as measured by the CTCAE v.5
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Concomitant medications assessment
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Imaging and pathology reports uploaded to Electronic Data Capture system
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Tissue and blood biobanking (if available at institution)
Evaluation during treatment
Follow up
Follow-up is planned at months 3 and 6, then annually after treatment. The following investigations should be performed:
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Adverse event evaluation and concomitant medications assessment with each follow up
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PSA at each follow-up
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EPIC-26, QLQ-C30, and EQ-5D-5L questionnaires at months 3 and 6, and years 1, 2 and 5 post-treatment completion
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Digital rectal exam (DRE), follow-up imaging and biopsies as clinically indicated
Intervention
General information
Patients allocated to the experimental study arm will undergo either a PSMA PET/CT or PET/MRI prior to treatment. Treatment (RT or RP) should be initiated within 10 weeks of randomization.
Conventional imaging guided intervention
A conventional imaging guided treatment plan will be defined for all patients prior to randomization. Those patients randomized to the conventional imaging arm will have their treatment planning and delivery based on conventional imaging (i.e. non-PSMA PET/CT based) as per investigator discretion. For high risk patients planned for RP, pelvic lymph node dissection (PLND) is recommended. For patients receiving primary or salvage RT, use of regional pelvic nodal radiation and adjuvant HT is at the investigator’s discretion and will be documented on a per patient basis.
PSMA PET/CT based intervention
PET/CT imaging
Investigational PET imaging radiotracer
This study will use 18F radiopharmaceuticals (18F-DCFPyL or 18F PSMA 1007) as available to participating sites through existing Health Canada approved supply arrangements. 18F labelled radiopharmaceuticals possess several advantages over 68-Gallium tracers: lower energy and shorter positron range allowing for higher image resolution, longer half-life (110 min vs. 68 min), the possibility of generating multiple doses from a single cyclotron synthesis run, and easier shipping to sites without radiochemistry/cyclotron facilities.
PET/CT imaging protocol
Imaging is to be performed on the institution’s most modern scanner, preferably with time-of-flight capabilities, within 3 weeks of randomization. The radiopharmaceutical will be injected by slow intravenous (IV) push followed by saline flush. Weight based (2–4 MBq/kg) and standardized dose (300 ± 60 MBq) approaches are allowed as per local practice. Images will be acquired 60–120 min following tracer injection. CT and PET images from the base of the skull to the proximal thighs will be acquired sequentially. Repeat imaging of equivocal sites of disease can be obtained up to 180 min post-IV.
Low-dose, non-contrast enhanced CT will be acquired along with the PET imaging, and will be used for attenuation correction and anatomical localization. For the PET, the number of beds and time-per-bed will vary according to the patient’s height, weight and scanner recommendations. Exact parameters should conform to the local standard-of-care, but typical parameters in the average patient are 6–8 bed positions, and approximately 3 min per bed position. Administration of IV furosemide (10–40 mg) prior to imaging or prior to repeat imaging to help clear bladder and ureteral activity is optional.
PET/CT interpretation, reporting and review
Images will be interpreted locally by an experienced nuclear medicine specialist with full knowledge of clinical history, and prior imaging. In addition to a standard local clinical report, an electronic Case Report Form (eCRF) will be completed where sites of suspected disease on PET will be correlated with CT findings on the PET/CT and a 4-point scale will be used to establish a standardized metric for the probability of malignancy, specifically: 1 = benign, 2 = equivocal, 3 = probably malignant, 4 = definitely malignant. All cases will be independently reviewed centrally for the purpose of quality control prior to any interventions.
PSMA PET/CT based intensification
Following local and central reads, results of the PSMA PET will be provided to the treating physician and the treatment plan intensified as appropriate to the PSMA PET findings as outlined in Fig. 2 and below. Note, in no case will de-intensification from the pre-PSMA PET pre-specified conventional imaging based plan be allowed. For example, for a patient who is planned for RP with PLND, RP without PLND is not allowed in the case of a negative PET. Similarly if regional nodal radiotherapy or adjuvant HT was part of the conventional imaging guided plan, those elements would continue even if the PET demonstrated no extra-prostatic disease.
No new lesions detected on PSMA PET
If no new lesions are detected, RT or surgery to proceed as planned based on conventional imaging. De-intensification of therapy is not permitted.
New local/regional lesions detected on PSMA PET
All visible lesions (probably and definitely malignant) to be included in a definitive treatment plan. Intraprostatic lesions are not considered new lesions unless they extend into seminal vesicles in a manner previously unknown.
Surgery
Proceed with RP, resection of involved lymph nodes, and regional lymph node dissection. If involved lymph nodes are not resectable due to surgical constraints, RT to involved LNs (including elective dose to the involved chain) is permitted but must be planned up front as part of first-line therapy in combination with surgery. Note that adjuvant RT in the absence of BF is not permitted.
Radiotherapy
Proceed with planned prostate/prostate bed (PB) RT +/− pelvic nodal RT as planned. (see Guidelines for Intensified Radiotherapy below).
Oligometastases (1–5 sites on PSMA PET) amenable to ablative therapy
Proceed with conventional imaging based radiotherapy or surgery. In addition, all detected metastatic lesions to be treated with SABR or surgery. For the purposes of this study, PET identified lesions that are contiguous (i.e. adjacent nodes in the same nodal chain; adjacent vertebral body lesions) will constitute 1 site.
Widespread metastatic disease not amenable to ablation
Treatment (RT) of primary disease (if present) is recommended. A change to continuous HT is also recommended, allowing local investigators discretion regarding additional Health Canada approved systemic therapy (e.g. abiraterone acetate, apalutamide, enzalutamide, docetaxel) after discussion with lead study PI’s. Ablative therapy to metastatic sites is not permitted, but palliative RT for symptom management is permitted.
Guidelines for intensified radiotherapy
Intensification of RT dose for detected lesions: Recommended dose objectives in for intensification of detected lesions on PSMA PET/CT are described in the following table in terms of equivalent dose in 2Gy per day fractions (EQ2D) based on the Linear Quadratic model of cancer cell survival and assuming an alpha/beta of 1.4. Specific techniques (for example inclusion of a brachytherapy boost) and fractionation (for example ultra-hypofractionated stereotactic RT) are at the discretion of the treating radiation oncologist in keeping with institutional standard of care practice unless otherwise specified. All institutions are required to undergoing credentialing with a standardized salvage RT case with dose intensification to a PSMA PET/CT involved lymph nodes. Participating centres are also required to have been previously credentialed for SABR for metastasis directed therapy through a prior REB approved clinical trial. Centres without local PSMA PET/CT or SABR capability are permitted to partner with other participating institutions for delivery of that component of care where needed. Given the safety and efficacy of dose escalation to imaging defined dominant intra-prostatic lesions as noted in phase II/III trials of mpMRI based DIL delineation [21, 22]; techniques that utilize a concomitant boost of DIL to allow escalation beyond EQ2D 78Gy to the whole gland are strongly recommended.
Target | Target Dose Range (Gy EQD2) | Fractionated RT (Gy EQD2) | HDR/LDR Brachytherapy Boost (Gy EQD2) | SABR (Gy EQD2) |
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Prostate tumor < 50% of prostate volume | (78–168) | (78–113) e.g. 77Gy/35 fractions with concomitant boost to 95Gy/35 fractions [21] | (115–140) intraprostatic boost optional at time of brachytherapy, (125% - GTV) | (92–168) e.g. 35Gy/5 fractions with concomitant boost to 50Gy/5 fractions [22] |
Involved pelvic or adjacent PA LNs (up to T12/L1) | (60–86) | (60–74) concomitant integrated or sequential boost (aim as high as possible within dose range while respecting OARs) | na | (65–86) 30–35/5# Concomitant boost |
Prostate bed GTV | (70–74) | (70–74) sequential boost only | na | na |
Bone metastasis | (66–110) | (66–74) concomitant if adjacent to pelvic RT fields | na | (66–110) 30-40Gy/5# 24Gy/2# (spine only) |
Remote LNs | (66–110) | na | na | (66–110) 30-40Gy/5# |
Lung mets (peripheral) | (190) | na | na | (190) 48Gy/4# |
Lung mets (central) | (86–168) | na | na | (86–168) 35-50Gy/5# |
Liver metastasis | (66 or more) | na | na | (66 or more) 30-60Gy/3–5# |
- For gross disease that has achieved a complete radiographic response to hormone therapy (e.g. enlarged lymph nodes), the original area of the disease should be treated to an EQD2 of 42-56Gy
- In general for stereotactic radiotherapy of metastases, a dose of 35 Gy in 5 fractions delivered in a conformal fashion and with dose homogeneity is an effective and safe dose for the majority of non-spine tumour targets. For spine metastases, a dose of 24 Gy in 2 fractions is highly recommended
- Radiation therapy details including OAR constraints are available in Appendix
See below for OAR constraints included in Appendix:
Organs at Risk
Major – Considered a planning priority (compromise PTV coverage to respect)
Minor - Strive to achieve WITHOUT compromising PTV coverage
In general, for OARS situated well below deviation thresholds, please apply the principle of As Low As Reasonably Achievable (ALARA) without compromising PTV coverage.
Sequential sum plans (final combined plan)
(Gy) | Rx 1.8-2Gy/Day | Rx 2.5Gy/Day | Rx 2.7Gy/Day | Rx 3Gy/Day |
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Major | Minor | Major | Minor | Major | Minor | Major | Minor |
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Rectum
|
D50% | 47 | 43 | 43 | 39 | 42 | 38 | 40 | 36 |
D25% | 66 | 60 | 60 | 55 | 58 | 53 | 54 | 49 |
D15% | 74 | 67 | 67 | 61 | 65 | 59 | 58 | 55 |
D0.5cc | 78 | 76 | 71 | 69 | 68 | 66 | 60 | 59 |
Bladder
|
D50% | 50(65) | 45(55) | 46(60) | 42(50) | 45 | 41 | 42 | 38 |
D25% | 66(68) | 61(64) | 60(65) | 55(60) | 58 | 54 | 55 | 50 |
D15% | 76 | 70 | 69 | 63 | 66 | 61 | 60 | 57 |
Bowel_bag
|
D200cc | 48 | 44 | 44 | 41 | 43 | 40 | 40 | 37 |
D3cc | 56 | 50 | 51 | 46 | 50 | 45 | 47 | 42 |
D0.1cc | 66 | 58 | 60 | 53 | 58 | 51 | 54 | 48 |
Femoral Heads
|
D1% | 55 | 40 | 50 | 37 | 49 | 36 | 46 | 34 |
- The values in bracket are for RT salvage post-prostatectomy with PB targets
Single plans (concomitant)
(Gy)
| 5 fractions | 15 fractions | 20 fractions | 22 fractions |
Major | Minor | Major | Minor | Major | Minor | Major | Minor |
Rectum
|
D50% | 25 | 23 | 37 | 33 | 40 | 36 | 41 | 37 |
D25% | 31 | 29 | 50 | 45 | 54 | 49 | 56 | 51 |
D15% | 34 | 32 | 55 | 50 | 58 | 55 | 63 | 57 |
D0.5cc | 36 | 35 | 57 | 56 | 60 | 59 | 65 | 64 |
Bladder
|
D50% | 27 | 24 | 39 | 35 | 42 | 38 | 43 | 39 |
D25% | 33 | 30 | 50 | 46 | 55 | 50 | 57 | 52 |
D15% | 37 | 34 | 56 | 52 | 60 | 57 | 64 | 59 |
Bowel_bag
|
D200cc | 25 | 24 | 37 | 34 | 40 | 37 | 42 | 38 |
D3cc | 29 | 26 | 43 | 38 | 47 | 42 | 48 | 43 |
D0.1cc | 33 | 29 | 49 | 44 | 54 | 48 | 56 | 50 |
Femoral Heads
|
D1% | 28 | 22 | 42 | 32 | 46 | 34 | 47 | 35 |
Gy (post RP)
| 25 fractions | 28 fractions | 33 fractions | 39 fractions |
Major | Minor | Major | Minor | Major | Minor | Major | Minor |
Rectum
|
D50% | 42 | 38 | 43 | 39 | 45 | 41 | 47 | 43 |
D25% | 58 | 53 | 60 | 55 | 63 | 57 | 66 | 60 |
D15% | 65 | 59 | 67 | 61 | 71 | 64 | 74 | 67 |
D0.5cc | 68 | 66 | 71 | 69 | 74 | 72 | 78 | 76 |
Bladder
|
D50% | 45 (60) | 41 (50) | 46 | 42 | 48 (65) | 44 (55) | 50 | 45 |
D25% | 58 (65) | 54 (60) | 60 | 55 | 63 (68) | 58 (64) | 66 | 61 |
D15% | 66 | 61 | 69 | 63 | 72 | 66 | 76 | 70 |
Bowel_bag
|
D200cc | 43 | 40 | 44 | 41 | 46 | 42 | 48 | 44 |
D3cc | 50 | 45 | 51 | 46 | 54 | 48 | 56 | 50 |
D0.1cc | 58 | 51 | 60 | 53 | 63 | 56 | 66 | 58 |
Femoral Heads
|
D1% | 49 | 36 | 50 | 37 | 53 | 39 | 55 | 40 |
- The values in bracket are for RT salvage post-prostatectomy with PB targets
Statistics and sample size calculations
Primary endpoint
Failure free survival (FFS) is defined as time from date of randomization to the date of BF, local/regional failure (pathology or conventional imaging), distant metastasis (conventional imaging), or death from any cause, whichever occurs first, or last known follow-up date. Event-free patients are censored at their last known follow-up date.
Primary endpoint analysis plan
FFS will be estimated using the Kaplan-Meier method and treatment arms compared using the stratified log-rank test. Stratification will be performed, for all analyses, using the following therapeutic cohort definitions: 1) high-risk RT, 2) high-risk RP, 3) salvage RT post RP without PLNRT, and 4) salvage RT post RP with PLNRT. A stratified Cox proportional-hazards model will be used to determine the hazard ratio (i.e., treated vs. controls) and to assess the effects of stratification factors [23]. The primary endpoint will be reported after the first of the following occurs: (1) it has been 5 years since the end of the accrual period of the study, or (2) there have been a total of 213 failure events reported (i.e., the expected number of events as per our sample size calculation reported below).
Secondary endpoints and analysis plans
Cancer control/efficacy
Overall survival will be estimated using the Kaplan-Meier method and treatment arms compared using the stratified log-rank test. The cumulative incidence estimator will be used to estimate time to event distributions for endpoints with competing risks (BF, local and regional failure, distant metastasis on conventional imaging, and cause-specific mortality). For all efficacy endpoints, Cox proportional hazards models will be used to determine hazard ratios (cause-specific hazard ratios in the case of endpoints with competing risks) and to assess the effects of stratification factors and other covariates of interest. All efficacy endpoints will be reported once 213 FFS events have occurred.
Adverse events
AEs will be graded using CTCAE v5. The number of patients with at least 1 grade 3 or higher AE will be compared between the treatment arms. All comparisons will be tested using a Chi-Square test.
Quality of life
Patients’ quality of life (QoL) will be assessed using the validated EPIC-26 and QLQ-C30 questionnaires. The QoL data will test the null hypothesis that guided treatment intensification results in no statistically significant differences between intervention arms for the four domain scores of the EPIC-26 instrument nor for the functional scale scores of the QLQ-C30. Any statistically significant differences will be interpreted for clinical significance by comparing them to the reported minimally important clinical differences for each instrument’s main domains.
Cost-effectiveness analysis
The primary analysis of economic evaluation will adopt the 5-year time horizon of the trial and will compare direct health care system costs incurred by patients in the two arms of the trial, taking the perspective of the Canadian Public Heath Care System. The primary effectiveness outcome for this analysis will be FFS at 5 years (5YFFS). We will calculate the expected incremental cost per 5YFFS. A number of secondary analyses will be conducted including (a) using QALYs as the outcome measure; (b) out-of-pocket and productivity costs incurred by patients as well as health system costs; and (c) caregiver/household spillover effects in the measures of both cost and outcome.
Statistical assumptions and sample size calculations
Participants are expected to be distributed among the four therapeutic cohorts in the following proportions: High-Risk RT, 40%; High-Risk RP, 25%; salvage RT (PB only) post RP, 15%; and salvage RT (PB + PLN) post RP, 20%. For each cohort, conventional imaging arm 5YFFS estimates are 80% for high risk RT [3, 4, 24, 25], 40% for high risk RP [26], 75% for salvage RT to PB alone [2], and 85% for salvage RT to PB with nodal radiation [2], respectively, for a pooled average of 70%.
Furthermore, we conservatively estimate the new lesion detection rate in the pooled PSMA PET/CT cohort to be 40% (per NCT03525288). Of these, 50% consist of lesions that would not have been treated with curative therapy, and would be amenable for definitive intensified therapy. Therefore at least 20% of patients in the experimental arm would potentially derive direct benefit from therapy intensification (untreated vs. treated). If we conservatively assume treatment of these disease sites to be between 40 and 45% effective in improving 5YFFS outcomes, we would expect to observe an absolute risk reduction between 8 and 9% in FFS, corresponding to a hazard ratio between 0.66 and 0.70, approximately.
In terms of modeling assumptions, we used a stratified, exponential, proportional-hazards model. Accrual was assumed to occur uniformly over 30 months following a 6- month ramp-up period of negligible recruitment. Following the accrual phase, the follow-up phase will last 5 years. Attrition was assumed to be 10% over the 5 years of follow-up. Our target was 80% power with a two-sided alpha of 5%. We estimate a total sample size requirement of 776 subjects (213 outcome events) in order to detect a hazard ratio of 0.68 (28% relative risk reduction and 8.4% absolute risk reduction in 5YFFS) over the pooled study sample and maintain adequate power under our assumptions. The 5YFFS is expected to be 21% in the experimental PSMA PET/CT arm, translating into a 79% failure-free rate at 5 years in the experimental arm vs. 70% in the conventional imaging arm.
Accrual/study duration considerations
This study is expected to accrue 30 patients per month so accrual would be completed in 30 months, after a 6-month ramp up period of negligible accrual. Full information for the FFS endpoint is expected to be mature for analysis approximately 6 years from study activation. Our recruitment plan includes pre-specified modifications if early accrual suggests that we are likely to fall short of our recruitment target. Accrual will be evaluated by the Data and Safety Monitoring Committee (DSMC) every 6 months following ramp-up. Interim accrual figures will be used to project accrual into the future. If our projections suggest that it is likely we will reach our accrual target within 3 years of study activation, the trial will continue without modifications. However, if our projections suggest it is likely we will reach our accrual target between 3 and 5 years from study activation, we will apply mitigation strategies as determined by the study executive. Finally, if our projections suggest we are unlikely to reach our accrual target within 5 years of study activation, we will consider potentially stopping the trial early.
Data and safety monitoring committee
The DSMC will meet twice a year at a minimum after study initiation to review patient accrual, general data quality, study conduct, and morbidity/adverse events. The DSMC will review reports of any serious adverse events and relevant charts to determine if such toxicity is related to treatment. If the DSMC deems that toxicity rates are excessive, then the DSMC can make a recommendation to modify, suspend or terminate the study. Membership of the DSMC includes representation from radiation oncology, medical oncology, surgical oncology, biostatistics, clinical research staff and ex-officio. Any members with potential conflicts of interest must withdraw from decision-making discussions related to the study.
Access to data
The final dataset will be available for public access. There are no contractual agreements limiting any investigator access to trial data.