Understanding the Mechanism of Action of Rucaparib in Cancer Treatment

Pharmacy Times interviewed Thomasina Morris, RPh, MHA, BCOP, pharmacist at Moffitt Cancer Center, on what rucaparib is used to treat and how its mechanism of action works to fight cancer.

Thomasina Morris: Rucaparib is used to treat ovarian cancer. It is a PARP inhibitor that works in both recurrent and second line ovarian cancer, fallopian tube cancer, peritoneal cancer.

The mechanism of action of rucaparib is basically that we have to understand the DNA repair. So, when we look at DNA repair, we look at how cells are fixed in the DNA. The PARP inhibitors focus on homologous recombination and also basic excisional repair.

So, when we understand, a PARP inhibitor, which the nomenclature is a poly (ADP-ribose) polymerase-1; it's one of the most abundant PARPs in our system, and there's also a PARP-2 and a PARP-3.

Now, the PARP-1 has a 500 affinity to repair. It brings in all these enzymes whenever there's a single strand break that occurs in our system. So, it brings in these enzymes, these enzymes fix the repair, and the cell continues. So, that's kind of the normality of our cell and reconfiguration.

The single strand breaks are usually repaired by the base excisional repair and the double strand breaks are repaired by the homologous recombination—that's how the cells survive. So, what happens is we bring in a PARP inhibitor, and when we bring in a PARP inhibitor, what will happen is that this PARP inhibitor will stop the repair, and it traps the PARPs—PARP-1 mainly— into the cell, and that affinity of trapping prevents the cell from repairing—and that's what we want. We want no repair in the cell because our cancer cells—the less they repair, the better off we are, showing progression-free survival.

So, when the PARP is trapped, it can't do anything else. So, it pretty much stays there, and in essence, what will happen is synthetic lethality occurs when you have not only BRCA mutation that's involved in preventing the repair of a cell, working with a PARP inhibitor, and also patients that are homologous recombinant deficient.

Normally, when one of those works, it happens to facilitate trying to stop the repair, but it may not stop it completely. It may still have an opportunity to fix something but when you combine more than 2, what will happen is that this will actually be an opportunity to stop repair of the cell altogether and cause cell death.