The Evolving Role of PARP Inhibitors in Ovarian Cancer - Episode 6
Whitney S. Graybill, MD, MS: There are a lot of similarities between rucaparib and olaparib, but with some very important differences. Both drugs inhibit PARP1, PARP2, and PARP3. Rucaparib is thought to have some increased inhibition as compared to olaparib. Also, rucaparib inhibits tankyrase-1 and tankyrase-2, which is unique. Both drugs have very similar half-lives, which means that both are dosed twice a day. There is a very similar volume of distribution for both drugs, around 100 L to 200 L. And protein binding is also anywhere from 70% to 80%.
Now, while both drugs are metabolized by the cytochrome P450 system, they’re metabolized by different pathways. Rucaparib is metabolized by the CYP2D6 enzyme and olaparib by CYP3A4 and CYP3A5. That’s an important distinction, because olaparib needs to be dose-adjusted if a patient is taking another drug that either increases, induces, or inhibits the CYP3A4/5 enzyme. Also, olaparib needs to be dose-adjusted in renal impairment.
Some of these differences are important because they affect the safety profile of the drug. With olaparib, it’s not uncommon to see an increase or an elevation in creatinine that we see in about 44% of patients on trials. With rucaparib, you tend to see a greater increase in creatinine in around 92% of patients, and you also see significant increase in ALT (alanine aminotransferase) and AST (aspartate aminotransferase) in about 75% of patients. In both of these instances, these findings tend to not be clinically significant. You can treat, through, a lot of these lab abnormalities, and they will eventually normalize with prolonged treatment.
Oliver Dorigo, MD, PhD: The ARIEL-2 trial investigated the value and efficacy of the PARP inhibitor, rucaparib, in patients who have platinum-sensitive ovarian cancer. The study had an intelligent design, since it did analyze the tumor tissue for defects in homologous recombination repair. In this study, this was done by what’s called loss of heterozygosity, which is a hallmark of homologous recombination deficiency. BRCA1 and BRCA2 genes are very much involved in homologous recombination repair, and once mutated, that repair is deficient. There are a number of other genes that do play a role in this very important pathway.
The rucaparib study identified a group of patients who had not BRCA1 or BRCA2 mutations, but otherwise significant changes and deficiency in homologous recombination repair. What was found in this study was that those patients who had BRCA1 and BRCA2 mutation indeed had a significantly better response to rucaparib and an increased progression-free survival compared to those patients who did not have BRCA1 and BRCA2 mutations. In addition, those patients who had high degrees of deficiency in homologous recombination repair likewise had a significant increase in progression-free survival compared to those patients whose homologous recombination deficiency was low without any BRCA1 and BRCA2 mutations.
I’ve used rucaparib in my patients in my personal practice occasionally. Rucaparib was approved just very recently. I personally have seen that patients are very interested and excited about receiving a drug like rucaparib that provides, based on the study, a meaningful increase in progression-free survival. Patients do appreciate the idea that we can, with a drug that’s well tolerated, increase the time to when they need a second treatment. The rucaparib approval is based on the presence of germline mutations or somatic mutations. We do find that about 15% of patients have germline mutations in BRCA1 and BRCA2, but there are at least 10% of patients who have somatic mutations in their tumor for which rucaparib is likewise a very meaningful drug.
Matthew Powell, MD: The ARIEL-3 trial was a large multi-center randomized phase III placebo-controlled trial that was a 2-to-1 randomization of 600 mg twice daily of rucaparib versus placebo. These patients were enrolled in 3 nested cohorts: a germline BRCA cohort, a homologous recombination deficiency cohort, and then what they called the intent-to-treat cohort.
The results of the trial for the germline BRCA-mutated patients showed a difference in progression-free survival of a 15.4 months versus 5.4 months. This represented a hazard ratio of 0.24. It was really quite exciting to see these big differences in the 2 groups.
When we look at the homologous recombination defect group, we see that it was around 16 months versus 5.4 months. Again, highly statistically significant with a good hazard ratio.
In the intent-to-treat population, we’re looking more around 9 versus 5.4 months, but it’s still highly statistically significant in that cohort. So, there were quite exciting results from this trial that really allowed all-comers to be evaluated regardless of BRCA status and showed benefit of treatment with rucaparib over placebo.
Whitney S. Graybill, MD, MS: Though PARP inhibitors have demonstrated increased activity in both the treatment and maintenance setting, we don’t have a whole lot of data in terms of PARP inhibitors as compared to standard-of-care chemotherapy. So, ARIEL-4 is a phase 3 randomized control trial evaluating rucaparib versus standard-of-care chemotherapy in patients with recurrent disease who had a BRCA1 or BRCA2 mutation and have had equal to 2 lines of prior chemotherapy. This trial is currently enrolling.
Transcript Edited for Clarity