#9 PARP Inhibitors for Prostate Cancer

Overview

About one man in nine will be diagnosed with prostate cancer in his lifetime. While optimism and progress in the last ten years have brought solace to some, the disease remains the second leading cause of cancer death among men in the US.

Treatment for prostate cancer typically depends on the stage. While some types of prostate cancer grow slowly – requiring little more than monitoring for changes or improvement – others are more aggressive and demand action in the form of radiation, surgery, hormone therapy, chemotherapy, or other treatments. Metastatic, castrate-resistant prostate cancer (mCRPC) is an incurable form of prostate cancer that continues to grow even when the amount of testosterone in the body is reduced to very low levels. Researchers are constantly looking for new treatment options for mCRPC and other refractory forms of prostate cancer.

PARP inhibitors are a group of pharmacological inhibitors of the enzyme poly ADP-ribose polymerase (PARP). They are drugs developed for multiple indications, including the treatment of heritable cancers. In women with ovarian and breast cancer with specific genomic defects (BRCA1 or BRCA2 positive mutations), PARP inhibitors have shown success and received approval as a targeted cancer therapy. While first-line cancer DNA-creating proteins in the body are often dismantled by chemotherapy, BRCA genes have a built-in backup up plan to repair cancer DNA. Repair is carried out by PARP proteins. Inhibiting said PARPs, therefore, causes cancer cell death. As approximately one in four men with prostate cancer appear to have similar genomic defects, the class of drugs began a journey of exploration in prostate cancer years ago.  

The PARP inhibitors rucaparib and olaparib have been demonstrated to delay the progression of prostate cancer in men with refractory cancer and BRCA mutations. Both were approved for the prostate cancer indication in May of 2020. Olaparib’s approval was based on results of the Phase III PROfound trial, which showed a statistically-significant and clinically-meaningful improvement in the primary endpoint of radiographic progression-free survival (rPFS) versus standard antiandrogen hormone therapies. Specifically, olaparib reduced the risk of disease progression or death by 66% and improved rPFS by 7.4 months compared to the 3.6 months of the comparison treatment. The FDA approval for rucaparib was based on data from the multi-center, single arm TRITON2 Phase II clinical trial. Rucaparib produced a 44% overall response rate and achieved a 55% PSA response rate – rates associated with better rPFS and overall survival (OS).

While prostate cancer continues to affect the lives of nearly 200,000 men per year in the US, the emergence of PARP inhibitors for this indication represents an enormous advancement for the disease. A handful of additional clinical trials exploring other PARP inhibitor compounds and their use in prostate cancer are ongoing – some exploring combination with other therapies. The approval of rucaparib and olaparib has opened the door to a world of therapeutic options and survival possibility for men around the world.

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