Efficacy of Saruparib (AZD5305) in High-Risk Prostate Cancer with a BRCA Mutation

Prostate cancer (prostate carcinoma) is one of the most common cancers in men. In many patients, the cancer is confined to the prostate or has spread only to the surrounding tissue (locally advanced). However, if the cancer exhibits certain characteristics, such as a high prostate-specific antigen (PSA) level or aggressive cell growth, there is a high risk that it will return or spread to other organs in the body (metastasize). A distinctive feature in some patients is a mutation in the BRCA genes (BRCA1 or BRCA2). These genes are normally responsible for repairing DNA damage. If they are defective, cancer cells can multiply more quickly, but they are also more susceptible to certain drugs that exploit this very repair defect.

The standard treatment for high-risk prostate cancer often includes radiation therapy (radiotherapy) combined with androgen deprivation therapy (anti-hormone therapy), which lowers the male sex hormone testosterone and thus deprives the cancer of its growth stimulus. The study drug saruparib (AZD5305) is a so-called poly-ADP-ribose polymerase inhibitor (PARP inhibitor) and has not yet been approved in Germany for the treatment of prostate cancer. PARP inhibitors block an enzyme that is also involved in DNA repair. In tumors with a BRCA mutation, the simultaneous blockade of the PARP enzyme and the loss of function of the BRCA genes result in the cancer cells being unable to repair their DNA damage and subsequently dying. The goal of this Phase 3 study is to determine whether saruparib, in combination with standard treatment (radiation therapy and anti-hormone therapy), is more effective than standard treatment alone. Patients will be randomly assigned to two groups within two cohorts. Cohort A includes patients with newly diagnosed high-risk prostate cancer or a recurrence following surgery (biochemical recurrence) who are receiving radiation therapy and hormone therapy. They will also receive either saruparib or a placebo. Cohort B includes patients with newly diagnosed very high-risk (locally advanced) prostate cancer who are receiving radiation therapy, hormone therapy, and the drug abiraterone. They will also receive either saruparib or a placebo.The study is “quadruple-blind,” meaning that neither the patients nor the doctors, examiners, nor data analysts know who is receiving the actual drug. This is intended to ensure that the results are objective. The primary endpoint of the study is metastasis-free survival for up to 93 months—that is, the length of time the patient lives without developing metastases.

Men aged 18 and older with confirmed prostate cancer that is classified as high-risk or very high-risk, or in whom the PSA level has risen again after surgery (biochemical recurrence), are eligible to participate. A confirmed BRCA1 or BRCA2 mutation in the tumor tissue is a prerequisite. In addition, patients must have completed a planned course of radiation therapy and must not have distant metastases.