Randomised, Double-blind, Placebo-controlled, Multicentre Phase III Study
of Olaparib Plus Abiraterone Relative to Placebo Plus Abiraterone as First-line Therapy in
Men with Metastatic Castration-resistant Prostate Cancer.

Prostate cancer is a heterogeneous disease and there is no cure for the
patients who reach the metastatic castration resistant
stage of the disease. Prostate cancer is the most common cancer in men in the
Netherlands.

Patients with metastatic castration-resistant prostate cancer will have a
median overall survival around the 3 years when starting
early with enzalutamide or abiraterone therapy. The median overall survival
within the same healthy patient population is around
the 15 years and therefore there is a need for an effective and well tolerated
treatment for this patient population.

Olaparib inhibits the protein PARP. PARP is responsible for DNA repair. Cancer
arises often from genetic abnormality and when
that happens the PARP effectiveness can be increased. Olaparib can prevent the
survival of cancer cells by preventing repair of
damaged DNA is, causing the cancer cells to die.
This phase Ill study will compare the effectiveness (based on radiographic
progression-free survival) of Olaparib in combination with Abiraterone compared
with abiraterone alone in patients with metastatic castration-resistant
prostate cancer.

The concept for treating mCRPC patients with the combination of olaparib and
abiraterone was largely based on the observation that
PARP inhibition plus androgen deprivation could significantly reduce the growth
of prostate cancer cells independent of HRR status, in both in vitro and in
vivo model systems.

To determine the efficacy of the combination of olaparib and abiraterone vs
placebo and abiraterone by assessment of rPFS in patients with mCRPC who have
received no previous therapy at mCRPC stage.

This study has been transitioned to CTIS with ID 2024-511144-86-00 check the CTIS register for the current data.

Primary objective: To determine the efficacy of the combination of olaparib and
abiraterone vs placebo and abiraterone by assessment of rPFS (Radiographic
progression-free survival) in patients with mCRPC (Metastatic
castration-resistant prostate cancer) who have received no prior cytotoxic
chemotherapy or NHA (New hormonal agent (abiraterone, enzalutamide)) at mCRPC
stage.

Phase Ill, dubbelblinded, randomized study. Randomisation 1:1 to:
- Olaparib (300 mg orally twice daily) and Abiraterone (1000 mg orally with 5
mg prednisone twice daily).
- Placebo (oral, twice daily) + Abiraterone (1000 mg oral with 5 mg prednisone
twice daily).

Approximately 720 subjects will receive treatment until progression.

Patients receive treatment with Olaparib 300 mg twice daily and abiraterone
acetate 1000 mg with 5 mg bid prednisone or
Patients receive treatment with Placebo twice daily and abiraterone acetate
1000 mg with 5 mg bid prednisone.

On several days during the study the patient will undergo the following
assessments:
Anamnesis (at the screening visit also the medical history), Physical
Examination, WHO performance status, Vital signs
(bloodpressure, pulse, temperature), weight, bonescan and CT or MRI scan, ECG,
Blood and urine assessments, tumor biopsy (if
necessary), MUGA/ECHO.


Risk of side effects which may be due to combination of olaparib and
abiraterone (and prednisone or prednisolone) seen in previous studies are:
Very common (>10% of the patients) side effects:
nausea, vomiting, constipation, asthenia, loss of appetite, back pain, bone
pain, diarrhea, cough, dyspnea, oedema peripheral, infections, pyrexia,
abdominal pain, arthralgia, anaemia, neutropenia.

Other observations:
cardiac events have occurred in this study, with more being observed in the
patient group who received both abiraterone and olaparib. However, the numbers
of events were very small, and the cause of these events is unclear.
Cardiovascular events have been reported in patients treated with abiraterone
alone.