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For Some Men with Certain Genes: PARP Inhibitors Instead of ADT

For Some Men with Certain Genes: PARP Inhibitors Instead of ADT

“We are using two PARP inhibitors, olaparib and rucaparib, in two clinical trials to maximize clinical benefit while avoiding the long-term toxicity of ADT.”

Nobody likes androgen deprivation therapy (ADT). Not doctors, and certainly not patients. ADT is a mainstay of treatment for advanced prostate cancer because it prolongs life for years, and sometimes even decades – but at a cost. Just a few of the many side effects of ADT (beyond the loss of testosterone itself ) are weight gain, depression, and a higher risk of diabetes, heart attack, stroke, and dementia.

So established, in fact, is ADT that although there are other forms of treatment for advanced and metastatic prostate cancer – including androgen receptor blockers, chemotherapy, new checkpoint-blocking immunotherapy drugs, and platinum chemotherapy drugs – ADT is still the gateway through which these drugs must pass. At some point, all men with advanced prostate cancer will start ADT, and they often never get off of it. If the PSA starts to rise and cancer starts to advance, they add another drug on top of it – but don’t stop taking the ADT.

We’ve been stuck with ADT because there hasn’t been a way around it. But now, we have entered the era of “precision oncology,” says medical oncologist Emmanuel Antonarakis, M.D.“Our goal is to use genetic information to tailor therapies for the right patients at the right time – something we couldn’t do before.” Precision treatment for prostate cancer requires knowing which faulty genes are involved in an individual man’s cancer, and knowing what to do with that information.

Some of the most common defective genes in prostate cancer are the DNA repair genes, whose job is to fix errors made as cells grow and divide. Genetic mistakes happen all the time in everyone, and it’s the job of these genes – including BRCA1, BRCA2, and ATM – to make sure that these mistakes are fixed before anything goes wrong. They do their jobs using a repair method called homologous recombination (HR). If one of these HR, or quality-control, genes stops working, harmful mistakes can eventually lead to cancer.

“In recent years, we have seen the advent of drugs called poly-ADP ribose polymerase (PARP) inhibitors,” says medical oncologist Mark Markowski, M.D., Ph.D. PARP inhibitors zero in on these faulty HR genes, and in someone whose cancer has one of these mutated genes, “inhibiting PARP can result in profound anti-cancer effects.”

Together, Markowski and Antonarakis are working – as Antonarakis puts it – “to exploit these HR mutations to develop non-hormonal therapies for men with recurrent and metastatic prostate cancer.” In other words, instead of shutting down the hormones that help drive the cancer, and then waiting for ADT to fail in these men, they are cutting right to the chase: going after the bad genes that caused the cancer in the first place. Without ADT.

“We are using two PARP inhibitors, olaparib and rucaparib, in two clinical trials being conducted to maximize clinical benefit while avoiding the long-term toxicity of ADT,” Antonarakis continues.

One trial, NCT03047135, is testing olaparib (a PARP inhibitor that has shown success in treating breast and ovarian cancer in women who have mutated BRCA1 and BRCA2 genes) without ADT in men with high-risk prostate cancer who have experienced a rise in PSA after prostatectomy. “In early results, we have observed that olaparib is well-tolerated and has very promising activity in some men,” says Markowski, “particularly – but not exclusively – in men who have mutations in BRCA2 and ATM, both of which are HR genes.”

A second trial, NCT03413995, also called the TRIUMPH study, is treating metastatic prostate cancer patients with the PARP inhibitor, rucaparib, “also in the absence of ADT,” Antonarakis says. “All men in the TRIUMPH study must have an inherited (or “germline”) HR gene mutation, and must feel comfortable postponing ADT.” This study has just begun enrolling patients, but already, “preliminary observations suggest potential benefit of PARP inhibition in this patient population, especially in men with germline BRCA2 mutations.”

These trials are being supported by Hopkins scientist Tamara Lotan, M.D., who is the lead pathologist on both studies. Lotan’s lab is conducting in-depth molecular analyses on tissue specimens to help determine which men will benefit the most from these PARP inhibitors.

To find out more about these studies, please call Rana Sullivan (410-614-6337) or Serina King (410-614-6139).

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