Expert Discusses Rucaparib Maintenance in Ovarian Cancer

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 <.0001).

OncLive: Can you please provide an overview of the trial?

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.Ledermann: 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.

What are the findings that you are presenting here at ESGO?

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.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.

Were there concerns with toxicity?

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. 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.

What impact do you believe these results will have on maintenance therapy in ovarian cancer?

I think what is important to stress here is that the toxicity is manageable in the vast majority of women. Although we need to reduce the dose of the drug in about 50%, they were able to continue therapy, and only about 13% of patients actually withdrew from the trial because of unacceptable toxicity. So, for the majority of patients who are not progressing, they can continue the drug for a long period of time without significantly affecting their quality of life. What we already have on this side of the ocean is a license of maintenance olaparib (Lynparza) in patients with BRCA-mutant ovarian cancer, but we have recently gotten the results of the NOVA trial with niraparib, which was again, in an all-comer population. That study showed that there was a significant benefit across all groups, so BRCA positive and BRCA wild-type. That has led to a license in the United States, and now the license for olaparib has been extended in the United States, and it is just as active as any other drug in the BRCA—wild-type population. So, we have 2 drugs that are licensed for all patients with platinum-sensitive ovarian cancer, responding to platinum, and then we have a maintenance PARP inhibitor.

What do you hope that oncologists take away from these results?

Rucaparib is the third of those, and I am quite confident that the company will get a license in that similar indication—so not only in BRCA positive, but also in wild-type, and with the spectrum of activity that I mentioned, with more activity in the LOH-positive than the LOH-negative [patients], but it is still active in all patients. I think we will have a new drug that is available for all patients with platinum-sensitive ovarian cancer, but the tricky thing for us as clinicians is to decide which of the 3 to use.I think we have waited a long time for confirmation that we have agents that will truly impact the PFS in women with ovarian cancer. We have known now for some years that patients with a BRCA mutation will respond very well to a PARP inhibitor, but now there is a growing body of evidence that we have seen with all 3 PARP inhibitors—rucaparib, niraparib, and olaparib—that these drugs are active beyond patients with a BRCA mutation.

Going forward, we have a completely new standard of care, namely giving a PARP inhibitor to patients who respond to platinum-based chemotherapy, leading to a significant improvement in their PFS.