DR MATULONIS: So the PARP field has been a remarkable field starting in around 2006-2007. And it’s really blossomed into this important class of drugs not only for ovarian cancer but for other types of cancers as well, namely, prostate cancer. I mean, I think that whole story is just fascinating and really represents a new class of agents for difficult-to-treat prostate cancer.

So how I envision is, there was some fumbling in terms of initial trial design with olaparib, different kinds of approval strategies taken, and Study 19 being the use of olaparib in maintenance therapy, try to distill a patient population that would be most sensitive, or have a cancer most sensitive to PARP inhibitor. And that is high-grade tumors — high-grade serous cancer, high-grade endometrioid cancers — that are responding to platinum, have been in response to platinum previously, and are currently in response to platinum, so really distilling a specific patient population.

And I think when you think more broadly of ovarian cancer, what has been, I think, a great — which is just superexciting moving forward — is that you can see the pathology. The pathologist gives you a diagnosis. And that pathology then gives you the sense of the genomics of the cancer. Think about high-grade serous carcinoma, low-grade serous carcinoma, endometrioid high-grade/low-grade, clear cell cancer, mucinous tumors. They all have their different underlying genomic underpinnings, where mucinous cancers have more KRAS mutations — they are more chemotherapy-insensitive — all the way to high-grade serous cancers, high-grade endometrioid cancers, which probably of them have this underlying homologous recombination deficiency kind of genomic picture.

About 20% to 25% of the whole group will be underlying BRCA, so either germline BRCA-positive tumor or somatic BRCA-positive. And then where I think it’s a little more murky is how to define that other portion of that 50% who are truly homologous recombination deficiency-positive. I think we’re in the very, very early understanding of how to predict for the sensitivity to a PARP inhibitor or to elicit the patient or cull out the patient and her cancer that’s going to be sensitive to PARP inhibitor.

And then adding something potentially to a PARP inhibitor to make that HR — maybe it’s deficient, but making it even more deficient, or taking an HR-proficient, meaning it’s got great DNA repair mechanisms going on, but making that HR-deficient through combination therapy.

DR LOVE: So for those of us who graduated from medical school more than 3 years ago, can you talk a little bit more about the biology of HR? Like, what really is it?

DR MATULONIS: Yes. Well, it’s a hugely complicated field. And I am very fortunate to have folks like Alan D’Andrea, who I work with at Dana-Farber, who are truly DNA repair experts. And yes, I think there are multiple ways that DNA repairs itself after breaks occur. Very simplistically, PARP inhibitors have multiple ways that they work.

One is through base excision repair, which helps repair single-strand breaks. If you inhibit PARP and, thus, base excision repair, those defects then get shunted into double-strand defects, which then rely on a very finely tuned, very elegant way of repairing DNA through homologous recombination, predominantly repairing the very critical double-strand breaks. So if a cell can’t fix a double-strand break, it essentially dies.

So if there’s something wrong with homologous recombination, such as any one of the number of proteins, but predominantly BRCA1 and 2, then that DNA does not get repaired. So if you either have a patient who’s got a mutation within BRCA1 or 2, where that protein is either absent or nonfunctioning, or not functioning 100%, then the cell doesn’t repair that double-stranded break.

But PARP inhibitors work other ways as well, and mostly through shunting the DNA breaks through other repair mechanisms that are not as fine-tuned and are more error prone, like things like nonhomologous enjoining, which are just clunkier and error prone and may not fix the problem. PARP inhibitors work. And they also work on PARP trapping, so when there’s a break in DNA and the PARP enzyme sticks to the DNA, it sticks and it has to fall off. But the PARP inhibitor basically allows that enzyme to stick to the DNA, and that doesn’t allow the DNA to repair itself.

Treatment strategies in the management of ovarian cancer (OC)

Mechanism of action of PARP inhibitors and importance of BRCA testing

PARP inhibitors as primary treatment after multiple lines of therapy

PARP inhibitors as maintenance therapy

Tolerability of olaparib

Treatment options after olaparib failure

Differences among PARP inhibitors

Future directions in OC research