Clinical evaluation of biomarkers as predictors of survival in metastatic prostate cancer patients

Prostate cancer (PCa) is the most frequent malignancy diagnosed in the Western
male population. Currently, it is difficult to predict which tumour will show
aggressive behaviour and which tumour will not. New diagnostic and prognostic
biomarkers for prostate carcinoma are being studied intensively. The biomarker
PCA3 is already used in clinical settings. Other new biomarkers such as
TMPRSS2-ERG and the new prostate cancer biomarker panel NGMP seem promising.
The response rate to androgen deprivation therapy for men with metastatic
disease is 80%-90%. Those remissions last for 2 or 3 years, but almost all
metastatic prostate cancer patients evolve towards an androgen-refractory state
resulting in death due to widespread metastases. This androgen-refractory state
is most accurately described as castration-resistant prostate cancer (CRPC).
Docetaxel-based chemotherapy is currently the first line standard of care for
CRPC patients. This therapy elicits a significant advantage in terms of overall
and progression-free survival. Unfortunately, the prolongation of survival is
only modest. Recently three second line treatments for patients with disease
progression after docetaxel treatment have been registered; cabazitaxel,
abiraterone acetate and enzalutamide, which have proven to prolong survival
significantly. Although other new therapies for CRPC patients are being
developed, the main issue with this development is the lack of qualified
surrogate endpoints for survival. PSA response does not predict long-term
benefit adequately. Reliable surrogate end points are being investigated in
order to reduce the time required to assess the efficacy of a new treatment and
appropriate selection of patients for clinical trials. Circulating tumour cells
(CTCs) are currently the most accurate and independent predictors of overall
survival (OS) in CRPC. These could also potentially assist in guiding earlier
discontinuation of ineffective treatment.
Results of a recent study (CHAARTED trial) have shown that patients with
high-volume, castration-sensitive PCa benefit from upfront docetaxel in terms
of survival, and therefore a combination therapy of androgen deprivation
therapy and docetaxel will be used in these metastatic PCa patients. We expect
more patients to get the combination therapy, that's why we want to include
this interesting group as well.

The primary aim of this study is to determine whether the biomarkers PCA3,
TMPRSS2-ERG and the NovioGendix prostate cancer biomarker panel (NGMP) are, by
themselves or as a panel of biomarkers, a reliable predictor of survival in men
with CRPC receiving systemic treatment or men with metastatic PCa receiving
combination therapy (androgen deprivation therapy and docetaxel). The primary
endpoint of this study will be overall survival (OS). The secondary endpoint of
this study will be biomarker response to treatment and biochemical and/or
radiological recurrence of disease.

In this study 260 male subjects with CRPC who are commencing post-hormonal
treatment (i.e. docetaxel, cabazitaxel, abiraterone or enzalutamide) and
metastatic PCa patients receiving combination therapy (androgen deprivation
therapy and docetaxel) will be enrolled from seven centres throughout The
Netherlands and one centre in Germany (Radboud University Hospital, Nijmegen,
Leids University Hospital, Leiden, The Netherlands Cancer Institute, Amsterdam,
Reinier de Graaf Hospital, Delft, Tergooi Hospital, Hilversum/Blaricum,
University Hospital Aachen, Aachen, Spaarne Hospital, Hoofddorp). Once enrolled
into the study, blood and urine samples will be collected before starting
treatment (week 0), after 15 weeks, 27 weeks and 42 weeks of treatment. Blood
and urine samples will be collected during routine outpatient clinical visits
and will be collected simultaneously with the blood collected for clinical PSA
measurement. Radiographic imaging evaluation will take place according to
standard clinical protocol for treatment follow-up. The blood and urine samples
will be stored until processed and tested for PSA, PCA3, TMPRSS2-ERG and the
NGMP at NovioGendix Research BV. These biomarkers will be compared to overall
survival (OS) and clinical findings. Supplemental analysis may include a
comparison of these biomarker counts with the PSA level response.

The intervention taking place consists of taking blood samples and first-catch
urine collection simultaneously with the blood collection for clinical PSA
measurement.