Personalizing enzalutamide (Xtandi®) therapy by understanding the relation between the decrease in the expression profile of a panel of preselected microRNAs, tumor related mRNAs and treatment response in patients with mCRPC (ILUMINATE)

Androgen deprivation therapy has been the standard of care for patients with
advanced prostate cancer. Androgen deprivation results in tumor re-gression,
relief of symptoms and a decrease in the concentration of pros-tate-specific
antigen (PSA) in most patients. Unfortunately, the response to androgen
deprivation therapy is not durable yet and disease progression occurs despite
effective suppression of serum testosterone. This disease state is called
castration-resistant prostate cancer (CRPC) and is almost always associated
with increased levels of prostate-specific antigen that suggests the
involvement of androgen-receptor signalling. Especially intra-tumoral androgen
levels are often increased in patients with progressive prostate cancer. CRPC
therefore remains sensitive to further manipulations of the androgen receptor
(AR) as demonstrated by the treatment efficacy of enzalutamide and abiraterone
acetate in this group of patients.

Enzalutamide is an androgen-receptor-signalling inhibitor. It is distinct from
the currently available anti-androgen agents in that it inhibits nuclear
trans-location of the androgen receptor. In a phase I-II trial enzalutamide had
significant antitumor activity regardless of previous chemotherapy status. The
phase III AFFIRM study confirmed the activity of enzalutamide in a fixed dose
of 160 mg once daily in men with metastatic CRPC (mCRPC) after che-motherapy
with a significantly longer median overall survival in the enzalu-tamide
treated group compared to the placebo treated group (18.4 months vs 13.6
months). More recently the phase III PREVAIL study confirmed the activity of
enzalutamide in mCRPC prior to chemotherapy. The benefit was shown for both
radiographic progression-free survival (HR 0.19; P<0.001) and overall survival
(HR 0.71; P<0.001) compared to the placebo treated group. Unfortunately a small
subset of patients is de novo resistant to en-zalutamide after three months
(approximately 5-10%). Another 10-15% of the patients are potentially
sub-optimally treated since they show progres-sion only shortly (within 6
months) after treatment. The biomarker PSA nowadays most frequently used may
not reflect the status of disease accurately. Up to 20% of men with CRPC have
an initial PSA increase before decline. Moreover the decline may occur up until
12 weeks after start of treatment or not at all. It is therefore urgent to find
early and more reliable indicators for treatment response assessment. Recently,
potentially promising prostate cancer specific biomarkers have been identified
that can be used to selected those patients at risk of harbouring prostate
cancer and to a priori select those patients who will respond to chemotherapy.

In this study we would like to explore whether early easily assessable and
potentially more predictive biomarkers can be used to discriminate between
patient who will develop 1. objective response; 2. stable disease or who are 3.
de novo resistant to enzalutamide therapy.
Additionally we would like to explore the relation between enzalutamide &
N-desmethylenzalutamide plasma concentrations and the decrease in these
potentially more predictive biomarkers.

Primary Objectives:
To explore whether the decrease in a panel of early easily assessable
biomarkers (PSA-mRNA, PCA3-mRNA and TMPRSS2:ERG gene fusion-mRNA, (currently
under development) ARv7 mRNA, ARwt mRNA, miR-21, miR-141, miR-200a, miRrumc95,
miRrumc87 and miRrumc4417) can discriminate between patients who are 1.
Optimally treated (response after 3 and 6 months of therapy) 2. Suboptimally
treated (progressive after 6 month of therapy) and 3 de novo resistant
(progressive after 3 months of therapy).
Secondary Objectives:
- To explore the relation between enzalutamide & N-desmethylenzalutamide plasma
exposure and the decrease in the se-lected biomarkers (the panel of mRNAs and
microRNAs)
- To explore the relation between selected biomarker response under
enzalutamide therapy and radiographic progression free survival
- To explore the relation between enzalutamide & N-desmethylenzalutamide
exposure and radiographic progression free survival

The study is a open label phase IV pharmacokinetics/ pharmacodynamics study in
chemotherapy naive patients with metastatic CRPC
A total of 40 patients will be enrolled into the study.

Patients participating in this study will have pharmacokinetic assessments at 1
month, 3 months and 6 months. On all
three days in the first ten patients a total of 10 blood samples will be
collected over 24 hours after enzalutamide
ingestion. Additionally, pre-dose blood samples will be collected for the
traditional and novel pharmacodynamic
biomarkers. All blood samples will be drawn from a once placed intravenous
cannula (absolute volume approximately
45ml). For the next 30 patients an adjusted less intensive PK collection
schedule will be derived based on the initial 10
patients. Participating in this study contributes to the knowledge on the most
adequate use of enzalutamide in
patients with metastatic castration resis-tant prostate cancer.

The risk-classification is assessed as negligible to the patient population
participating in this study.
Enzalutamide is registered in the Netherlands for mCRPC prechemotherapy at the
same dose as used in this study.
The intervention embraces the measurement of pharmacokinetic and
pharmacodynamic biomarkers and response.
Besides the venapunction there is no additional risk for the patients who
participate in this study protocol.