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Researchers Studying PARP Inhibitor, Hormone Therapy in Prostate Cancer Patients with Gene Fusion


Having pinpointed a genomic rearrangement that triggers prostate cancer, researchers at the University of Michigan Comprehensive Cancer Center and elsewhere have launched a clinical trial to study whether patients harboring this mutation respond better to an experimental PARP inhibitor combined with hormone therapy or to hormone therapy alone.

A team of UM researchers led by Maha Hussain are currently conducting a Phase II study in which metastatic hormone-resistant prostate cancer patients will first be tested to gauge whether they harbor a genomic rearrangement that causes a fusion between the TMPRSS2 gene and the ERG gene. After establishing study participants' status for this gene fusion, patients will be randomized to receive either AbbVie's PARP inhibitor veliparib in combination with the corticosteroid prednisone and the hormone therapy abiraterone, or just the prednisone/abiraterone regimen.

The aim of the study is to characterize the extent to which prostate cancer patients with this gene fusion respond differentially to either hormone therapy or to the combination of hormone therapy and velaparib. Additionally, researchers will analyze whether the hormone therapy/velaparib combination is superior to just hormone therapy based on patients' gene fusion status.

Currently, the trial is being conducted at 11 sites in the US and is actively recruiting patients. Investigators aim to enroll around 170 patients. Arul Chinnaiyan, director of UM's Center for Translational Pathology and a study investigator, told PGx Reporter that there are currently 40 patients enrolled in the study.

In 2005, researchers led by Chinnaiyan first discovered the link between TMPRSS and ERG gene fusions and prostate cancer. Approximately 50 percent of prostate cancer patients harbor this gene fusion. The gene rearrangement blocks receptors of the hormone androgen, which disrupts normal development of prostate cells and causes cancer.

In a 2010 paper in Cancer Cell, Chinnaiyan and colleagues described sequencing the genome-wide location of the androgen receptor and the gene fusion in prostate cancer cells. In this paper, the investigators reported that the gene fusion plays a central role in the development of prostate cancer by inhibiting androgen receptor expression and preventing the receptor from signaling normally. Because androgen receptors are involved in the development of male sexual characteristics, the inhibition of these receptors causes prostate cells to stop growing and induces cancer.

Chinnaiyan noted that previously published data suggest that prostate cancer patients with TMPRSS and ERG gene fusions respond better to the hormone therapy than those without this marker. This is further "supported by the biology that fusions are under androgen regulation," he noted. Abiraterone, marketed under the brand name Zytiga, is used to treat castration-resistant prostate cancer patients who don't respond to medical or surgical treatments that lower testosterone, and works by reducing the amount of androgens made by the prostate tumor, the adrenal glands, and the testes.

Furthermore, data from preclinical studies suggest that patients with this gene fusion respond better to PARP inhibitors, a class of drugs that block enzymes from repairing DNA damage, allowing cell survival. These drugs have shown to be particularly efficacious in cancer patients harboring BRCA1, BRCA2, and PALB2 tumor mutations who lack the ability to repair DNA damage, or those that lack the tumor suppressor PTEN.

According to Chinnaiyan, prostate cancer patients who harbor the TMPRSS and ERG fusion are more likely to have loss of PTEN or activation of the PI3K pathway.

In addition to comparing whether patients with this particular gene fusion respond better to veliparib plus hormone therapy or just hormone therapy, the study will also track the decline of prostate specific antigen in the treatment arms. PSA is often elevated in prostate cancer patients.

The trial is slated for completion in two years. AbbVie, which recently split from Abbott with the firm's drug assets, donated veliparib for the trial. The trial is being funded by grants from the National Cancer Institute, US Department of Defense, and the Prostate Cancer Foundation.