PARP Inhibitors: The Move Towards Genetic Targeted Treatment for Prostate Cancer
Heading into the recent 13th Annual Interdisciplinary Prostate Cancer Conference and Other Genitourinary Malignancy Conference Daniel P. Petrylak, MD spoke of poly(ADP-ribose) polymerase (PARP) inhibitors possessing the potential to change the standard of care for prostate cancer (PCa).1 This is certainly a claim worth taking a closer look at, as well as who in the PCa population to which it may apply.
What is PARP?
The first question is what exactly is PARP and what role can inhibiting it play in fighting prostate cancer? (Yes, I know this is actually two questions, but bear with me – this is complicated stuff). PARP is a protein contained within cells and its job is to help damaged cells to repair their DNA. This is usually a good and useful thing, but what about when the cells have mutated into something that damages the body – i.e. cancer cells? In this case, PARP can actually serve to repair the cancer cells. Cancer cells are actually prone to DNA damage.
“Genomic instability is a hallmark of cancer, and often is the result of altered DNA repair capacities in tumor cells. DNA damage repair defects are common in different cancer types; these alterations can also induce tumor-specific vulnerabilities that can be exploited therapeutically.”2 What this means in more layman terms is that if a treatment can be devised to inhibit the PARP protein from repairing the DNA of cancer cells, the growth of cancer can be stymied.3
How can PARP be used for targeted therapy?
PARP inhibitors are considered a type of targeted therapy or precision medicine, meaning that they focus on a specific feature of the cancer cells. The hope is that the targeted therapy will spare normal cells and cause fewer side effects, as well as inhibit the growth of cancer in a way that other treatments are unable to.
Researchers originally focused these drugs on breast and ovarian cancers, specifically patients found to have faulty BRCA genes. There was a very good reason for this. When one or both of the BRCA1 and BRCA2 genes is faulty the mutation can increase the risk of certain cancers. The natural role of these genes, like PARP, is cell repair. When the genes are faulty, they no longer fulfill this role. Because the cancer cells resulting from faulty BRCA genes are already inhibited in their ability to repair themselves, introducing a PARP inhibitor further increases the potential to block cell repair and thus to kill off cancer cells.4,5
How does it apply to prostate cancer?
As many of you know, the BRCA mutation is also often found in prostate cancer patients. Researchers are now turning what they learned in developing PARP inhibitors for these other cancers to PCa (you are not alone if you are thinking treatments often seem to be developed for other cancers and only tested for PCa later). At this point, there are two PARP inhibitors FDA approved for treating prostate cancer - Rucaparib (Rubraca) and Olaparib (Lynparza) - but several others in various stages of clinical trial.
Olaparib (Lynparza) is already approved for the treatment of breast and ovarian cancer. Before its prostate cancer approval, it was given FDA Breakthrough Designation for BRCA1 and BRACA2 mutated castration-resistant prostate cancer. Previous studies found positive results in castration-resistant patients who previously had cancer progression with Zytiga or Xtandi for those with BRCA mutated genes, as well as the ATM gene (another gene involved in cell repair).6,7 Those receiving Olaparib had a radiographic progression-free survival representing a 66% reduction in disease progression compared to either doctor's choice of Zytiga or Xtandi (whichever the patient had not previously failed on) plus prednisone.8
Niraparib (Zejula) has also been granted Breakthrough Designation and has gone through phase II trials. While early in the study process, results have been encouraging. The lead author of the study stated: “These preliminary results suggest that PARP inhibition with niraparib may play an important role in the treatment of men with metastatic castration-resistant prostate cancer who have mutations in DNA-repair genes.”9
Of course, not all PCa patients have these genetic mutations, but the numbers are not inconsequential. “Overall, about 20% to 22% of men with metastatic prostate cancer are predicted to have these mutations either in their bodies or in their tumors. That’s the basis for using DNA damaging agents, like platinum chemotherapy or PARP inhibition, to take advantage of those vulnerabilities in the cancer cell, and to benefit patients with longer survival and freedom from disease progression and spread” said Andrew J. Armstrong M.D., professor of medicine and professor of surgery, Duke Cancer Institute, Durham, NC.10
How else can these treatment developments help?
In addition, there is a possibility that PARP inhibitors may be combined with other treatments to aid those without the faulty DNA repair genes. Dr. Armstrong speaks of how androgen receptors help with DNA repair, thus drugs that block them can mimic the impact the BRCA2 mutation has on DNA repair. Combined with PARP inhibitors, androgen receptor blockers can aid those PCa patients without the gene mutations. Studies on this effect are now underway.11
While studies have focused on metastatic castration-resistant prostate cancer, researchers also hope that these treatments can be extended to earlier stage PCa.12 What these potential advances illustrate is that, as Dr. Andrew states: “There are incentives now to do both hereditary and tumor-specific genetic testing and counseling to open the door for patients that could have clinical benefits from PARP inhibitors as well as to help in the early detection and treatment of patients with familial cancer syndromes.”13
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