Phase III study of [18F]PSMA-1007 positron emission tomography for the detection of prostate cancer lesions in patients with biochemical recurrence after previous definitive treatment for localized prostate cancer

Other than skin cancer, prostate cancer is the most commonly diagnosed solid
organ malignancy in men; in the United States, approximately 191,000 new
diagnoses and over 33,000 deaths are expected in 2020, according to the
American Cancer Society. The prevalence and mortality rates in western Europe
are similar. Despite a five-year survival rate of approximately 98%, recurrence
of prostate cancer is common, up to 40-50% in some populations.
The diagnosis of prostate cancer recurrence after prior definitive therapy is
typically based on an increase in blood prostate-specific antigen (PSA)
concentration, based on serial measurements. For localization of tumor lesions
in patients with rising PSA, different diagnostic imaging methods are available
(computed tomography [CT], magnetic resonance imaging [MRI], bone scintigraphy,
positron-emission tomography [PET]). While the available diagnostic methods
provide reasonable diagnostic accuracy at later stages with high PSA levels,
none of these methods provides the required sensitivity and accuracy to detect
recurrence at early stages (e.g., PSA below 1-2 ng/mL).
PET/CT imaging with the non-specific tumor marker C-11-choline or its analogue
F-18-fluorocholine has been used for more than a decade for imaging prostate
cancer. Choline PET/CT is recommended by the National Comprehensive Cancer
Network (NCCN) [1] and the European Association of Urology (EAU) [2] for the
detection of sites of recurrence of prostate cancer after initial radical
treatment. According to the meta-analysis of 14 articles by Treglia et al [3],
pooled detection rate of prostate cancer for radiolabeled choline PET/CT is
58%, increasing to 65% in patients with PSA doubling time of 6 months or less,
and 71% in patients with PSA levels greater than 1 ng/mL.
Recently, PET with radiopharmaceuticals targeting prostate-specific membrane
antigen (PSMA) have been reported to detect prostate cancer lesions with high
sensitivity. PSMA is a type II membrane glycoprotein that is expressed in all
types of prostate tissue, and a number of pharmacophores have been developed
that bind to PSMA with high specificity. As such, PSMA is a promising target
for PET imaging in prostate cancer. Von Eyben et al. [4] recently conducted a
meta-analysis to evaluate the detection rate, diagnostic test accuracy, and
adverse effects of Ga-68-HBED-CC-PSMA (Ga-68-PSMA-11) PET/CT or PET/MRI for
staging of patients with prostate cancer and for restaging of patients with
rising PSA after initial treatment. Fifteen studies with 1,256 patients met the
inclusion criteria. Seven studies of staging PET/CT or PET/MRI detected a
regional site of cancer for 203 of 273 patients (74%). Nine studies of
restaging PET/CT detected sites of recurrence in 799 of 983 patients (81%) with
a 50% detection rate (74 of 147 patients) for restaging patients with PSA of
0.2-0.49 ng/mL, and a 53% detection rate (56 of 195 patients) for restaging PSA
of 0.50-0.99 ng/mL. None of the studies reported complications from PET/CT
imaging.
Ga-68 has several shortcomings as a radiolabel, including short half-life and
non-ideal energies for PET imaging, and PSMA-11 has high renal clearance, which
is not optimal for pelvic imaging. Recently, the F-18 labeled PSMA ligand
PSMA-1007 was described as a tracer for PET imaging [5]. [18F]PSMA-1007
demonstrates high labelling yields, outstanding tumor uptake and fast,
non-urinary background clearance [5]. Radiation dosimetry in three healthy
volunteers resulted in an effective dose of 4.4-5.5 mSv per 200-250 MBq. In
comparison to other PSMA-targeting PET-tracers, [18F]PSMA-1007 has reduced
urinary clearance enabling excellent assessment of the prostate. Similar to
F-18-DCFPyL and with slightly slower clearance kinetics than PSMA-11, favorable
tumor-to-background ratios are observed 2-3 h after injection. Giesel et al.
[5] were able to successfully validate diagnostic [18F]PSMA-1007 findings by
histopathology. In their study, [18F]PSMA-1007 PET/CT detected 18 of 19 lymph
node metastases in the pelvis, including nodes as small as 1 mm in diameter.
In an ongoing comparative trial (ABX-CT-301, NCT04102553), 200 patients with
suspicion of recurrent prostate cancer were included, of whom 191 underwent
[18F]PSMA-1007 PET/CT. The imaging results are compared to 18F-fluorocholine
PET/CT for the detection of prostate cancer lesions. Patient enrollment and
imaging is complete, but clinical follow-up in that study is still ongoing, and
no efficacy results are available. A preliminary safety assessment found a
total of six adverse events (AEs) contemporaneous with the PSMA-PET imaging;
none of those AEs were reported by the investigator to be related to the study
drug. There were no serious AEs.
Further details about [18F]PSMA-1007 can be found in the investigator*s
brochure which contains comprehensive information on the study drug.

There are two co-primary study objectives:
• Region-level positive predictive value (PPV) defined as the percentage of all
PET-positive regions containing at least one true positive lesion (exactly
localized correspondence between [18F]PSMA-1007 PET imaging and the reference
standard), regardless of any co-existent false positive findings within the
same region, out of all regions containing at least one [18F]PSMA-1007 PET-
positive finding. Regions to be considered in the analysis are prostate bed,
pelvic lymph nodes, skeleton, and other distant sites (extrapelvic lymph nodes
and viscera).
• Patient-level *correct detection rate* (DR) defined as the percentage of
patients who have at least one true PET-positive lesion (exactly localized
correspondence between [18F]PSMA-1007 PET imaging and the reference standard),
regardless of any co-existent false positive findings, out of all patients who
are scanned.

The primary objectives will be assessed in a blinded manner using 3 independent
readers for imaging and an independent clinical panel for *truth*.

Secondary objectives
• to assess the correct detection rate and PPV of the clinical investigator
for[18F]PSMA-1007 for metastatic prostate cancer lesions (patient-based
analysis)
• to assess detection rate and PPV of [18F]PSMA-1007 by body region for
prostate cancer lesions (region-based analysis: prostate bed, pelvic lymph
nodes, skeleton, and other distant sites [extrapelvic lymph nodes and
viscera]). Reads by investigator and 3 independent blinded readers.
• to assess the safety profile of [18F]PSMA-1007

This is a multi-center, open-label, nonrandomized study in patients with
biochemical recurrence of prostate cancer, incorporating independent evaluation
of PET imaging and an independent truth panel to determine clinical truth. The
analysis population includes three cohorts of patients: approximately 60
evaluable patients to be recruited into this protocol (ABX-CT-303EUR),
approximately 60 evaluable patients to be recruited into a companion study
(ABX-CT-303US) to be conducted in the United States, and all evaluable patients
who completed study ABX-CT-301. Newly recruited patients will undergo the
following procedures:
1. Screening
2. PET/CT imaging with [18F]PSMA-1007
3. A follow-up visit one day after PET imaging for safety assessments
4. In selected patients, a follow-up visit for MRI or biopsy
5. 6 months of clinical follow-up (collection of all additional diagnostic
information including imaging, as required for clinical purposes);
investigators will be encouraged to seek biopsy confirmation of positive
findings in [18F]PSMA-1007 PET

The true disease state at the time point of imaging will be determined by an
expert panel on the basis of all relevant information from pre-inclusion to the
end of the follow-up period, excluding data from [18F]PSMA-1007 PET.

Recruited patients will undergo the following procedures:
PET examination with [18F]PSMA-1007
6 months follow-up (collection of all additional diagnostic information
including imaging, as required for clinical purposes). During follow-up,
selected patients will undergo multiparametric magnetic resonance imaging.
Other selected patients may undergo biopsy.

Safety assessments will include:
adverse events
clinical laboratory (blood chemistry, hematology, urinalysis)
12-lead electrocardiogram
Vital signs
Safety assessments will end the day following the PET examination.

In this study, participating patients with suspicion of prostate cancer
recurrence or persistence will undergo one PET/CT examination with
[18F]PSMA-1007.
The use of [18F]PSMA-1007 in prostate cancer patients has been reported in
several hundred patients without relevant safety signal. The radiation exposure
with [18F]PSMA-1007 is comparable (0.019 mSv/MBq) to that of fluorocholine
(0.017 mSv/MBq) and fluorodeoxyglucose (0.020 mSv/MBq). In addition to the
radiation exposure from fluorine-18, there is the additional exposure from
computed tomography, which varies from approximately 2 mSv for a low-dose CT to
approximately 10 mSv for a diagnostic CT. The total radiation exposure is well
below the limit of 30 Gy often considered to be an acceptable upper limit for
subjects in a clinical trial. Overall, the risk for adverse events is
considered to be low for patients participating in this trial.
Patients participating in this trial may have a personal benefit from
undergoing [18F]PSMA-1007 PET/CT. The imaging results will be made available to
treating physicians and may lead to a more accurate diagnosis and treatment.
Considering the potential personal benefit, the severity of the underlying
disease, and the low probability for severe and serious adverse events, the
benefit-risk ratio of this study is regarded as acceptable and positive.
This study will commence during the COVID-19 pandemic and the intended study
population (males typically older than 60 years of age) constitutes a risk
group for COVID-19. In general, patients with recurrence or persistence of
prostate cancer have a higher morbidity and mortality than the general older
male population and could benefit from a better understanding of the location
and extent of their disease. We consider the short-term risk of COVID-19 to
patients and study staff to be reasonable, as the study visits all require only
minimal interaction between patient and staff. However, because the pandemic
situation is very fluid and varies by study site, study investigators are
encouraged to incorporate appropriate mitigation strategies where appropriate
for the local condition. Such mitigation strategies might include combination
of visits 1 and 2 or a temporary hold on study recruitment while a local
outbreak is brought under control.