A phase III, open label, randomized study to assess the efficacy and safety of Olaparib (Lynparza*)versus Enzalutamide or Abiraterone acetate in men with metastatic castration-resistant prostate cancer who have failed prior treatment with a new hormonal agent and have homologous recombination repair gene mutations

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.

In a small percentage of all the prostate tumors, there is a mutation in the
following genes: BRCA1, BRCA2, and ATM (<15%).
Mutations in these genes result in tumors that are deficient for homologous
recombination, making them suitable for the treatment with a PARP inhibitor,
wherein the synthetic lethality process can be utilized.

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 III study will compare the effectiveness (based on radiographic
progression-free survival) of Olaparib compared with enzatulamide or
abiraterone (choice of the investigator) in patients with metastatic
castration-resistant prostate cancer with mutations in one of the HRR genes.

To determine the efficacy (as assessed by rPFS) and safety of olaparib versus
investigator choice of enzalutamide or abiraterone acetate in men with
metastatic castration-resistant prostate cancer who have failed prior treatment
with a new hormonal agent and have homologous recombination repair gene
mutations.

Phase III, open-label, randomized study. Randomisation 2:1 to:
- Olaparib (300 mg orally twice daily)
- Enzalutamide (160 mg orally od) of Abiraterone (1000 mg orally met 5 mg
prednison bid).

Approximately 340 subjects will receive treatment until progression. Adter
discontinuation of olaparib patients will enter the follow up phase. Patients
who are treated with Enzalutamide or Abiraterone can after progression switch
to olaparib after discussion with the physcian (cross over arm)

Treatment with Olaparib 300 mg bid or Enzalutamide 160 mg orally od or
Abiraterone acetate 1000 mg od with 5 mg bid prednisone.

On several days during the study patients 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).

Related side effects are:
Very often (> 10%): anemia, neutropenia, lymphopenia, nausea, vomiting,
dyspepsia, diarrhea, decreased appetite, headache, dizziness, dysgeusia,
fatigue (among which asthenia). Increased bloodcreatinin, increase of average
corpusculair volume.

Often (1-10%): trombocytopenia. stomatitis, stomach pain.

Further have been reported:

secondary myelodysplastic syndrome or secondary acute myeloïde leukemia (in
most cases fatal); esp. in case of predisposing factors (history of cancer of
dysplasia of bone marrow, simultaneous use of DNA damaging treatments and
radiotherapy).
Pneumonotis, (in some cases fatal), esp in case of predisposing factors
(lungmetastases, underlying lungdisease, history of smoking, former chemo- and
radiotherapy)