Mechanism of Action and Efficacy of PARP Inhibitors in Ovarian Cancer


Bhavesh Shah, RPh, BCOP; and Thomasina Morris, RPh, MHA, BCOP, discuss the mechanism of action and efficacy for the 3 PARP inhibitors used to treat patients with ovarian cancer: olaparib, rucaparib, and niraparib.

Bhavesh Shah, RPh, BCOP: Thomasina, what are the approved drugs and how can they be used in combatting ovarian cancer?

Thomasina Morris, RPh, MHA, BCOP:Thanks, Bhavesh. Well, like you said there is a plethora of PARP inhibitors right now, and there’s more to come as we know. For ovarian cancer, we have 3: olaparib, rucaparib, and niraparib. All these PARP inhibitors have gone to the extent of having similar indications, being treatment after either 2 to 3 lines, or as maintenance. Most of these PARP inhibitors are geared toward germline or somatic BRCA mutations. As you said, 2005 is when they found the first PARP, and now with 17, and there’s PARP1 or PARP2. PARP1 is the most abundant; that’s the one that comes and fixes the DNA so that these PARPs can facilitate DNA replication, where the PARP inhibitor can come and stop that replication.

For us historically, we have not been part of the SOLO1, SOLO2, or ARIEL3 studies. However we were part of the NOVA study, and we got the first patient on niraparib. That patient, there was a first indication for ovarian cancer and technically they had low platelets, low hemoglobin, etc. It actually was phenomenal for us at that time, even though the olaparib had already been approved. For ovarian cancer, this level of medication that we’re seeing in oncology is phenomenal; now we know our patients with ovarian cancer are going to be genetically tested. We know they’re going to look at BRCA to see if they’re mutated, 1 and 2. Now we have a little bit more of the molecular functionality of the homologous recombinant deficiency, which now pulls in more information to show that these patients may have better progression-free survival overall. Having a BRCA mutation, they will have a benefit, and this will give them progression-free survival up to 12 to 24 months in some cases. This is phenomenal because the last indication for a new drug we got was Avastin [bevacizumab] approximately 20 years ago.

Bhavesh Shah, RPh, BCOP: We’ve been using maintenance therapy in ovarian cancer; to educate our viewers, I think about how ovarian cancer has a very high recurrence rate. Because of this minimal residual disease, there’s been this concept of maintenance therapy that we know benefits patients. Unfortunately, we tried Taxol, which we can’t keep patients on forever because of the toxicities. Then we have, as you said, the gentler option bevacizumab, however there are still toxicities associated with it. Now we have PARP inhibitors, which have really been huge game changers.

Like you said, maybe we should talk a little bit about the mechanism. We know that essentially what PARP is, it’s poly-ADP ribose polymerase enzyme, which normally functions to do repairs on transcription and DNA repair. Having that pathway being inhibited essentially will lead to this exogenous and endogenous DNA damage, leading to cell death. Essentially, having that activity being lost, which we know happens in BRCA-deficiency predominantly, is more common in patients with ovarian and breast cancer. That’s how PARP inhibitors really work. Now we know that BRCA1 and BRCA2 penetration goes beyond just ovarian and breast; we know that it’s something that also may be in prostate, pancreatic, and GI [gastrointestinal] malignancies and melanoma. There’s so much more that PARP hits or a prevalence can be found in different malignances. It’s a really important mechanism to understand and have targets in the market.

This transcript has been edited for clarity.

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