[18-F]-Fluordihydrotestosterone PET and [18F]-prostate specific membrane antigen in metastasized castrate resistant prostate cancer

The critical pathway that drives prostate cancer growth throughout the natural
history of the disease is the androgen receptor (AR), which is present and
actively signaling even when the tumor is castration-resistant. The recognition
that the AR continues to signal in patients with castration-resistant
metastatic disease is one of the most transformative contemporary biologic
discoveries in advanced prostate cancer. The centrality of the AR to tumor
progression in metastatic castration-resistant prostate cancer (mCRPC) has
resulted in the development of novel AR-targeted therapies, such as androgen
biosynthesis inhibitors and pure antiandrogens, that prolong life, reduce pain,
and enhance quality of life. Hence, we recognized the clinical need for
detecting pharmacodynamic changes caused by treatment with each class of drugs;
developing an early indicator of response; and developing predictors of
survival.

Means by which AR continues to signal despite castrate levels of serum
testosterone could be through AR overexpression, mutation, and
ligand-independent activation, among others. [18F]fluorodihydrotestosterone
(FDHT) is a positron-emitting radiotracer that provides an innovative way of
directly imaging the primary molecular engine of mCRPC. Preliminary studies
have demonstrated its safety, feasibility, pharmacokinetic properties, accuracy
at identifying prostate tumor, and utility in drug development. Before further
efforts to clinically qualify this imaging biomarker are undertaken, however,
analytic validation studies in regards to the biomarker*s reproducibility
between centers and patients, and correlation with AR expression, must be
undertaken. We hypothesize that variability, if present, may be attributed to
one or more of the following variables: intrinsic properties of the tracer,
tumor AR overexpression, endogenous tumor androgen levels, or tumor perfusion.

Such imaging biomarkers could serve as pharmacodynamic indicators (identifying
drug effects), as prognostic indicators (in stratifying patients by risk), and
as response indicators (identifying active drugs). This proposal advances a
significant body of previous work on development of imaging biomarkers for
prostate cancer an This study builds on those efforts, fulfills regulatory
requirements for biomarker development, and addresses a significant unmet
clinical need. If successful, we will have analytically validated the first
imaging biomarker in prostate cancer that directly images the cancer cell by
means of its growth engine.


Sub-study:
[18F]Fluorodihydrotestosterone ([18F]FDHT) is a relatively new oncological
tracer used to perform Positron Emission Tomography y ([18F]FDHT PET) scans. A
series of radiotracers has been developed to visualize the androgen receptor of
which 16-beta-[18F]-fluoro-5-alphadihydrotestosterone was selected for clinical
evaluation. Dihydrotestosterone is the predominant form of testosterone in the
prostate gland. Biodistribution studies in rats and baboons showed
prostate-to-blood activity concentration ratios up to 7:1, and androgen
receptor binding. The activity of FDHT in the region of the prostate peaked at
30-90 minutes post injection. At 60 minutes there was a high ratio of prostatic
activity to soft tissue, blood and bone (>6:1, >3.5:1 and >7:1 respectively).
Uptake decreases after the administration of cold testosterone. However, time
course studies have not been conducted in relation to treatment and response. A
noninvasive method for measuring changes in the androgen receptor (AR) in
metastatic prostate cancer may be particularly important for assessing the
effects of drugs that act through or directly on the androgen receptor.

Accurate quantification of the [18F]FDHT signal is important beyond visual
image interpretation. For quantification of PET tracers, non-linear regression
analysis is the gold standard. However, its complexity makes it unsuitable for
application in daily clinical practice; moreover, it is not compatible with the
whole body acquisitions typically required in patients with metastasized
disease. Simplified measures applicable in whole body settings can and should
be validated versus the reference technique. Perfusion related parameters are
often important in pharmacokinetic modeling. Sofar, we have used 15O-water PET
to measure these variables. However, [15O]-water PET requires an on-site
cyclotron, and this is not available in the majority of hospitals.
Alternatively, DCE-MRI is a clinically available, and it measures
perfusion-related parameters as well. However, it needs to be shown how these
DCE-MRI parameters correlate with [15O]-water PET. We expect that, upon
validation, incorporation of DCE-MRI will provide an even more comprehensive
multiparametric quantitative image since this adds information on permeability
and perfusion and with higher spatial resolution than is feasible with PET.

Taken together, a profound understanding of the [18F]FDHT pharmacokinetics
could lead to an optimization of the [18F]FDHT PET diagnostic potential;
integration of DCE MRI and PET parameters would allow for a clinically feasible
method with PET-MRI. This is essential to improve the quality of the imaging
research towards personalized therapy strategies for prostate cancer patients.

The objectives of this trial are:
1. To define the performance characteristics of FDHT PET in patients with
metastasized castrate resistant prostate cancer
(mCRPC).
(a) To demonstrate the kinetics of displacement of the tracer off of the
androgen receptor(AR) in patients treated with enzalutamide.
(b) To demonstrate the variability of the imaging characteristics
(c) To preliminary explore early post-treatment changes in FDHT and PSMA uptake
and MRI in patients treated with abiraterone and other androgen biosynthesis
inhibitors.
(d) To explore predictive value of baseline FDHT and PSMA uptake before
AR-targeted treatment.
2. To define the relationship between FDHT uptake and PSMA uptake and tumor
diffusivity as assessed by whole-body MRI.
3. To define the relationship between FDHT uptake, AR expression, serum
androgen levels, androgen levels in biopsy specimens, CTC enumeration, ARV7
presence, and ARV7 nuclear localization.

Sub-study:
The aims of the sub-study are to create a tracer kinetic model for
quantification of [18F]FDHT, to simultaneously validate a simplified
quantitative method, and to investigate the concordance of MRI- and PET-based
perfusion related parameters.

This is a multi-center, prospective observational study in 105 patients with
metastasized castrate resistant prostate cancer. Reproducibility and
variablitiy of FDHT-PET will be addressed using a test-retest FDHT-PET study
without intercurrent treatment on day 1 and 2. If unstable FDHT scans (a
relative difference is recorded of more than 0.15 in 5 patients or more)
patients will be scanned at day 1 and 8. When still unstable patients will be
scanned at day 1 and 22. However if there is a relative difference is less than
0.15 the cohort will be expanded with an additional 50 patients. All patients
wil also undergo a DW-MRI at baseline to define the correlation between FDHT
and tumor diffusity.

Patients in the expanded cohort will undergo one baseline FDHT-PET, DW-MRI,
and/or PSMA PET before start of AR-targeted therapy, one PSMA-PET and/or DW-MRI
4 weeks after start of treatment and one DW-MRI and or PSMA PET at progression.
These will serve to explore the predictive value of FDHT PET and postreatment
changes in PSMA-PET and DW-MRI. Blood is taken to define the relationship
between FDHT uptake, serum androgen levels, CTC enumeration, ARV7 presence, and
ARV7 nuclear localization. Optional FDHT guided biopsy is performed to
correlate FDHT-PET and serum androgen levels with AR expression and androgen
levels in biopsy specimens.


Sub-study:
A monocenter, prospective observational study in 10 patients with metastasized
castrate resistant prostate cancer. Dihydrotestosterone uptake
[18F]FDHT, perfusion ([15O]-water), and DCE-MRI parameters will be measured
quantitatively. Accuracy of blood and plasma activity
concentration, plasma metabolite measurements derived from arterial and venous
samples as well as the reliability of using Image Derived Input Functions
(IDIF) for quantification of [18F]FDHT kinetics will be tested. Dynamic PET and
MRI scanning will be performed using 2 tracers for PET ([15O]-water and
[18F]FDHT) and 1 contrast agent for MRI (Gadovist).

The total radiation dose will be between 20 and 31 mSv. Although this is
relatively high we think that it is acceptable for this particular study in
view of this specific population and high scientific impact. Cannulation of the
venous canulla will be performed by experienced clinicians who have followed
training at the Department of Anesthesiology. In spite of this, occasionally
these cannulae may cause a hematoma. The biopsy of a metastasis will be
performed under local anesthesia by an experienced interventional radiologist
(CT-guided).

Sub-study:
The total radiation burden of the extra scan will be about 0.5 mSv making the
total radiation dose between 14.5 mSv and 23.5 mSv. The extra scan will only be
performed in patients not undergoing an PSMA scan. Cannulation of the venous en
arterial cannulae will be performed by experienced clinicians who have followed
training at the Department of Anesthesiology. In spite of this, occasionally
these cannulae may cause a hematoma.