Ovarian Cancer - Episode 2
Shannon Westin, MD: Now to the PARP inhibitors, which is where we’ve had the most new data over the last year to 2 years, especially over these last few months. As a quick review of the mechanism of action: The PARP itself is involved in single-stranded break repair. In a normal cell, when you inhibit PARP, it doesn’t necessarily affect the machinery of the cell or affect the way the cell repairs its DNA breaks. However, if you have single-stranded breaks that are not able to be repaired, you get accumulation of double-stranded breaks. Those double-stranded breaks are going to be repaired by homologous recombination. That gets into when we have a cell that cannot utilize homologous recombination, there’s a homologous recombination deficiency. Then PARP inhibition seems to work the best.
What causes that homologous recombination deficiency? There’s a couple of different mechanisms, but generally it involves pathway members that are in the DNA-damaged repair pathway, such as BRCA, which is our most common, but we can also see other pathway members like ATR or ATM, RAD51D, RAD51C. All those are involved in homologous recombination repair, and if they’re aberrant, if they’re nonfunctioning, that cell can be damaged by a PARP. You hit the cell with PARP, it has its single-stranded breaks accumulate, it develops new double-stranded breaks, but then it cannot repair and that leads to cellular catastrophe, genomic instability, and cell death.
Because of that, studies were initially focused on BRCA in mutant tumors, but as we’ve learned, more and more tumors may potentially be sensitive to PARP inhibition. There are a number of frontline trials that have been reported. I’m not going to get into too much detail. There’s tons of detail on this slide, and it’s more meant to give an overview of the 4 major trials that looked at PARP inhibition in the up-front setting. We’re going to go through each in a little bit of detail, but here are some of the highlights.
The PRIMA and SOLO-1 trials were single-agent, true maintenance studies that were started after the patients had a response to therapy. SOLO-1 was only in BRCA mutant, whereas PRIMA was in all comers. PAOLA required the patients to have received chemotherapy with bevacizumab, then have a response, and then olaparib could potentially be added in a randomized fashion. Finally, VELIA was the only study to combine a PARP inhibitor, veliparib, with chemotherapy in the up-front setting, potentially followed by veliparib maintenance. That’s the difference among all those, and you can see the hazard ratios. The bottom line is that they all work. The question is this: where do they work the best? What it comes down to and what I’m going to be excited to hear from our panelists today is this: how do you make those decisions? How do you decide whether you’re going to give chemotherapy with PARP? Or how do you decide when you’re going to stick to a PARP maintenance? I’m hoping they’re getting ready to tell me all these answers.
Transcript edited for clarity.