Jonathan Ledermann MD, FRCP
The success of PARP inhibitors continues to grow in ovarian cancer as rucaparib becomes the latest agent to show a significant improvement in progression-free survival (PFS) in the maintenance setting.
Results of the randomized phase III ARIEL3 study were presented at the 2017 International Meeting of the European Society of Gynaecological Oncology (ESGO) in Vienna, Austria, by lead author, Jonathan Ledermann, MD.
In the ARIEL3 trial, patients with platinum-sensitive, high-grade ovarian, fallopian tube, or primary peritoneal cancer were randomized in a 2:1 ratio to receive rucaparib or placebo. Endpoints were prospectively assessed across 3 cohorts. In the first, patients had BRCA-positive tumors, including both germline and somatic alterations (n = 196). In the second group, patients were homologous recombination deficiency (HRD)-positive, which could include BRCA-mutant or wild-type with a high loss of heterozygosity (LOH; n = 354). A third group assessed all-comers in the intent-to-treat population (n = 564).
For patients with germline or somatic BRCA mutations, there was a 77% reduction in the risk of progression or death with rucaparib versus placebo (HR, 0.23; 95% CI, 0.16-0.34; P
<.0001). In the HRD group, risk reduction with rucaparib was 68% (HR, 0.32; P
In an interview with OncLive
during the meeting, Ledermann, professor of medical oncology, UCL Cancer Institute, London, discussed these results, as well as the future of PARP inhibitors in the maintenance setting for patients with ovarian cancer.
OncLive: Can you please provide an overview of the trial?
: ARIEL3 is a trial with rucaparib which is one of the PARP inhibitors that we already know is active in ovarian cancer, it’s licensed in the United States for the treatment of BRCA
-mutated ovarian cancer. What the ARIEL3 trial is looking at is maintenance therapy with rucaparib, and it follows a number of trials that have been done using this concept of giving patients chemotherapy and then maintaining the response and freedom from progression by using a PARP inhibitor.
So, ARIEL3 was actually the third randomized trial in that setting. The trial took women with recurrent endometrial to serous ovarian cancer who were platinum-sensitive; they then were treated with platinum-based chemotherapy. After a partial response or complete response, they were randomized either to rucaparib or to placebo and the primary endpoint was PFS.
Now, one of the differences about ARIEL3 from some of the other trials is that all of the patients had tumor BRCA status looked at, and also, whether they had the presence of an HRD phenotype. And that was determined by measuring the amount of genomic scarring through the amount of loss of heterozygosity. That was used as a stratification factor, and it was also used as an exploratory factor to look and see whether LOH-positive patients did better than LOH-negative. That was the slight difference in the design of the trial.
What are the findings that you are presenting here at ESGO?
The primary endpoint was the investigator-assessed PFS, and we looked first at the BRCA
-mutant cohort, which is somatic or germline BRCA
mutated, and if that was positive, then the HRD cohort, which also included BRCA
wild-type but patients who were LOH positive, and then lastly, the all-comers.
The trial showed that there was a significant improvement in PFS. First, in the BRCA-mutant population, there was an HR of 0.23 and an 11.4-month extension in the median PFS. We then looked at the HRD cohort and the all-comers, and in both groups, we saw a significant benefit of maintenance rucaparib. So, for all patients with platinum-sensitive disease there was an HR of 0.36 in favor of maintenance rucaparib.
Were there concerns with toxicity?
The toxicity is always an issue with any of these drugs, particularly drugs that are going to be given for a long period of time. It is important that they are tolerable. Now, all of the PARP inhibitors have reported toxicity. Rucaparib also has toxicity, although, a slightly different pattern of toxicity, compared to niraparib (Zejula), for example, with less myelotoxicity but a bit more vomiting and nausea.