Optimizing abiraterone (zytiga®)therapy by exploring the relation between an early biomarker-drug exposure-as a predictor for drug response in patients with mCRPC (OPTIMUM study)

Androgen deprivation therapy has been the standard of care for patients with
advanced prostate cancer. Androgen deprivation results in tumor re*gression and
relief of symptoms and a decrease in the concentration of prostate*specific
antigen (PSA) in most patients. Unfortunately, the response to treatment is not
durable and virtually all patients develop castration*resistant prostate cancer
(CRPC). However, as demonstrated by the efficacy of abiraterone acetate, CRPC
remains sensitive to further manipulations of the androgen receptor (AR).
Abiraterone acetate, a prodrug of abiraterone, is a selective and irreversible
blocker of cytochrome P450 C17 (CYP17), a crucial enzyme in testosterone and
estrogen synthesis, resulting in virtually undetectable serum and intratumoral
androgen levels. Unfortunately, also the response to abiraterone acetate is not
durable yet. Moreover, a substantial group of the patients treated with
abiraterone is initially not responsive to the therapy with abiraterone in the
pre* and post chemotherapy setting.
Since the currently used fixed dose results in a substantial interpatient vari*
ability (40.5 * 140.6%) in drug exposure the unresponsive patients might be
those that are underexposed to abiraterone. Additionally, in the PK * PSA *
survival modeling a relation between drug exposure, PSA decrease and sur*vival
was present. Therefore, in this study we would like to explore the rela*tion
between abiraterone plasma concentrations (as an early pharmacoki*netic
biomarker) and drug response (primarily based on radiology and sec*ondary on
biochemistry).
Additionally, we would like to investigate whether other exploratory early
easily assessable pharmacodynamic (=PD) biomarkers in combination with the more
traditional PD biomarkers could give earlier insight in treatment response.
The traditional biomarkers measured are PSA, dehydroepiandrosterone (DHEA),
lactic acid dehydrogenase (LDH) and alkaline phosphatase (AP).
The exploratory biomarkers measured are circulating tumor mRNA, as de*tected by
PSA mRNA, PCA3 mRNA, TMPRSS2:ERP gene fusion mRNA and the currently under
development ARv7 (splice variant 7) mRNA and ARwt (full length) mRNA in
peripheral blood mononuclear cells (PBMC).

Primary Objectives:
*To explore whether early abiraterone exposure (AUC) is corre*lated to
treatment response after 3 months and 6 months of therapy (primarily based on
radiographic response (RECIST re*sponse: SD, PR, CR) and secondary on
biochemistry (*25% de*crease in PSA). In case of only bone lesions: SD is
defined as no new lesions; PD is defined as * 2 new lesions (PCWG2 criteria)

Secondary Objectives:
*To explore the relation between novel early and easily assessa*ble biomarkers
(PSA*mRNA, PCA3*mRNA, TMPRSS2:ERP gene fusion*mRNA, (currently under
development)ARv7 mRNA and ARwt mRNA) and treatment response after 3 months and
6 months of therapy*
To explore whether the degree of reductions in these novel bi*omarkers are
related to abiraterone exposure (AUC) after 3 and 6 months of therapy
*To explore the relation between traditional PD biomarkers (se*rum PSA, DHEA,
LDH, AP) and treatment response after 3 and 6 months of therapy
*To explore whether the degree of reductions in PSA, DHEA, LDH, AP are related
to abiraterone exposure (AUC) after 3 and 6 months of therapy

The study is an open label phase II intervention pharmacokinetics/ pharma*
codynamics study in patients with metastatic CRPC.
A total of 50 patients with metastatic CRPC will be enrolled into the study.

no therapeutical intervention. Exclusively determine pharmacokinetics and
pharmacodynamics of abiraterone for the indication according to the drug label
(CRPC)

Patients participating in this study will have pharmacokinetic assessments at 1
month, 3 months and 6 months (one pre-dose sample per PKday). 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 40ml). Participating in this
study contributes to the knowledge on the most ade*quate use of abiraterone
acetate in patients with metastatic castration resis*tant prostate cancer. The
risk*classification is assessed as negligible to the patient population
participating in this study. Abiraterone acetate is registered in the
Netherlands for mCRPC pre*chemotherapy 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.