A study of opaganib in addition to darolutamide in participants with metastatic hormone resistant prostate cancer, selected for the presence of a specific biomarker.

ACTRN 12624001458527

Brief Summary

This study is taking a novel approach to using predictive biomarkers to select people for lipid (fat) targeted treatments, to attempt to overcome hormonea chemical substance produced by glands in the endocrine system that regulates various functions in the body resistance in people with metastatic hormone resistant prostatea walnut-shaped gland in the male reproductive system that is responsible for producing semen - a bodily fluid that acts as a vessel for sperm transport during ejaculation cancera disease where abnormal cells split without control and spread to other nearby body tissue and/or organs.

There is increasing evidence that abnormal lipid (fat) metabolism promotes the growth of prostate cancer cellsthe basic structural and functional unit of all living things. We have previously shown that abnormal patterns of blood-borne lipids (called ceramides) can identify a group of people with metastatic hormone resistant prostate cancer who are likely to be resistant to the usual hormone treatments: abiraterone and enzalutamide. In the DARO-LIPID study, we will first identify which participants with metastatic hormone resistant prostate cancer have the high ceramide lipid signature through a bloodthe red bodily fluid that transports oxygen and other nutrients around the body test. Participants who do not have this lipid signature will receive usual care by their oncologista doctor who specialises in the study, diagnosis and treatment of cancer. Participants with this lipid signature who consent to the study will all receive darolutamide as standard of care. Participants will then be randomly split into two groups with one group also receiving the lipid drug called Opaganib to target the abnormal lipid changes and the second group receiving a placebo.

The study is designed to see if Opaganib can increase the number of people who respond to darolutamide, and increase the time that they get benefit from the treatment. We will also look at how the Opaganib is affecting lipid/fat metabolism in the body/tumour.

Intervention/Treatment

• Drug: Darolutamide
• Drug: Opaganib
• Drug: Placebo

Inclusion Criteria

1. Metastatic adenocarcinomacancer arising from mucus-producing glands in organs of the prostate defined as:
   • Documented histopathology of prostate adenocarcinoma (no features of neuroendocrine
     carcinomacancer arising from tissues that line organs), OR,
   • Metastatic disease typical of prostate cancer.
2. Castration-resistant prostate cancer (defined as disease progressing despite castration by
   orchiectomyremoval of one or both testicles, also known as orchidectomy or ongoing luteinizing hormone-releasing hormone agonist or antagonist).
3. Progressive disease with rising PSA defined by PCWG3 criteria (sequence of 2 rising
   values at a minimum of 1-week intervals) or progression of disease radiologically.
4. Evidence of metastases on bone scana type of medical imaging that uses a radioactive tracer to detect bone conditions or abnormalities and/or CT scan beyond pelvic lymphadenopathyswollen lymph nodes/glands, also known as adenopathy.
5. Participants are allowed to have had previous chemotherapya cancer treatment that uses drugs to kill or slow the growth of cancer cells, while minimising damage to healthy cells with docetaxel in the
   hormone sensitive setting only.
6. Acceptable liver function:
   • Bilirubin less than or equal to 1.5 times upper limit of normal (CTCAE Gradea description of how abnormal cancer cells and tissue look under a microscope when compared to healthy cells 1 baseline).
   • AST (SGOT) & ALT (SGPT) less than or equal to 3 x upper limit of normal (ULN) (CTCAE
     Grade 1 baseline).
   • Participants with Gilbert’s syndrome may be included if the total bilirubin is less than 3x
     ULN and the direct bilirubin is within normal limits.
7. Acceptable kidneya pair of bean-shaped organs in the abdomen that are responsible for filtering excess water and waste products from the blood and converting them into urine to be removed from the body function indicated by serum creatinine less than or equal to 1.5 X ULN
   (CTCAE Grade 1 baseline).
8. Acceptable hematologic status:
   • Absolute neutrophil count is greater than or equal to 1.0 x 109 /L
   • Platelet count is equal to or greater than or equal to 75 x 109/L (CTCAE Grade 1 baseline)
   • Hemoglobin is greater than or equal to 90 g/L
9. ECOG performance status 0-2
10. Life expectancy of at least 3 months
11. Willing to complete all study requirements, including standard of care treatment
12. Willing to complete Health Related quality of lifethe overall well-being of a person diagnosed with cancer, encompassing both physical and emotional aspects of health (HRQL) questionnaires UNLESS is
    unable to complete because of literacy or limited vision
13. Signed, written informed consenta process in which a patient receives detailed information about a procedure or treatment, including its potential risks, benefits, and alternatives. The patient then has the opportunity to understand the information and voluntarily agree to the procedure or treatment.