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ASCO 2019 Data on PARPi
PARP Inhibitors in Recurrent Ovarian Cancer: What’s New at ASCO 2019

Released: June 24, 2019

Expiration: June 22, 2020

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Currently, 3 PARP inhibitors, olaparib, rucaparib, and niraparib, are approved by the FDA for treating patients with ovarian cancer in various settings. At the ASCO 2019 Annual Meeting, data from several important studies of PARP inhibitors in recurrent ovarian cancer were presented. In this commentary, I briefly review the data and share my thoughts on these studies.

ARIEL3
The first study I am going to discuss is the phase III ARIEL3 trial, which was designed to measure the impact of rucaparib as maintenance therapy in recurrent ovarian cancer after response to platinum chemotherapy. In the original analysis we published, rucaparib maintenance therapy significantly improved the primary endpoint of PFS compared with placebo. In the current analysis, we wanted to measure the impact rucaparib maintenance therapy might have on subsequent lines of therapy. The key question here is how long the benefit from maintenance therapy with rucaparib can persist into the next line of therapy. Of more importance, if a patient receives a PARP inhibitor and then has disease progression, is her disease still sensitive to the next line of therapy? 

The exploratory endpoints evaluating subsequent lines of therapy included PFS2 (defined as the time from initial randomization to disease progression on the next line of therapy or death), time to first subsequent therapy, and time to second subsequent therapy. Not surprisingly, what we saw was that each of these exploratory endpoints evaluating postprogression treatment outcomes was significantly prolonged by rucaparib maintenance therapy relative to patients on placebo. These findings are important because they demonstrate no detrimental effect on subsequent lines of therapy from using a PARP inhibitor as maintenance therapy.

We also had the opportunity to update the safety data in this analysis. We found, with extended follow-up, that the safety profile of rucaparib maintenance therapy was consistent with our previous report. Overall, the current analysis of ARIEL3 showed that the benefits from rucaparib maintenance therapy persisted into subsequent lines of therapy with a consistent toxicity profile.

AVANOVA2
The next study I would like to address is the randomized phase II AVANOVA2 trial, which examined the impact of adding bevacizumab to niraparib for treating patients with platinum-sensitive recurrent ovarian cancer. The concept of this trial was to look at the opportunity to improve outcomes by combining an anti-angiogenic agent with a PARP inhibitor, both of which have proved to be active in treating recurrent ovarian cancer. The first phase of this study identified a recommended phase II dose, and the second phase aimed to assess PFS, the primary endpoint of the trial. Overall, AVANOVA2 was a relatively small study with just under 100 patients enrolled but with important outcomes. The patient population in this trial was slightly enriched for the presence of BRCA mutations. Typically, BRCA mutations are present in 15% to 20% of patients with ovarian cancer, and in AVANOVA2, about a third of the patients were BRCA positive, with most of the mutations being somatic. Predominantly, patients had received 1 or 2 lines of prior therapy. 

The outcomes from this trial are interesting and consistent with a previous report comparing cediranib plus olaparib vs olaparib in the same setting. In AVANOVA2, a substantial improvement in investigator-assessed PFS was observed with the addition of bevacizumab to niraparib. Looking at subgroup analysis based on BRCA status, the PFS benefit was more prominent in the wild-type BRCA patient cohort vs those with tumors harboring mutated BRCA. One plausible reason for this finding could be that BRCA-mutated platinum-sensitive recurrent disease responds well to PARP inhibitors and adding bevacizumab might not yield much additional benefit. When looking at subgroup analysis based on homologous recombination deficiency (HRD) status, the PFS benefit was similar in patients who were positive or negative for HRD. The investigators also looked at subgroups based on chemotherapy-free interval. In patients with short (6-12 months) or long (> 12 months) intervals, a significant PFS benefit was observed with the combination regimen, although it was greater in those with a short chemotherapy-free interval. These results probably reflect the impact of bevacizumab, which has activity in both platinum-sensitive and platinum-resistant recurrent ovarian cancer.

In my opinion, AVANOVA2 is an important trial, and it begs the question whether there could be a chemotherapy-free option for patients with platinum-sensitive recurrent ovarian cancer. Indeed, several studies are in progress or being planned to test this hypothesis, one of which is the ongoing phase III NRG-GY004 trial looking at single-agent olaparib vs cediranib plus olaparib vs platinum-based chemotherapy in women with platinum-sensitive recurrent ovarian cancer. Another study is the planned phase III AVATAR trial that will compare niraparib plus bevacizumab with standard of care in the same setting. It is exciting to have new potential combination modalities involving PARP inhibitors in platinum-sensitive recurrent ovarian cancer.

SOLO3
The last study I am going to review is SOLO3, a phase III trial of olaparib vs nonplatinum single-agent chemotherapy in women with platinum-sensitive recurrent ovarian cancer harboring germline BRCA mutations. SOLO3 is a highly anticipated trial because it asks the question whether a PARP inhibitor is better than chemotherapy in recurrent disease. This is a very interesting concept because we know that PARP inhibitors have substantial activity in recurrent ovarian cancer. The question is: How do they compare with chemotherapy?

We saw in SOLO3 that the ORR (assessed by blinded independent central radiographic review) for olaparib was pretty remarkable at 72% compared with 51% for chemotherapy, with most of the responses being partial response. The increased response rates were seen in patients with 2 prior lines of chemotherapy as well as those with 3 or more prior lines of chemotherapy. Although nonplatinum chemotherapy has better response rates in patients with platinum-sensitive disease than those with platinum-resistant disease, it still begs the question whether platinum-based chemotherapy should have been used instead as the control arm in this trial. Olaparib was also better than nonplatinum chemotherapy in terms of secondary endpoints, including PFS and time to subsequent lines of therapy. Importantly, there was no difference in quality of life between the 2 arms, and the toxicity profile of olaparib was very consistent with previous findings.

Overall, SOLO3 is an important study showing that a PARP inhibitor is better than nonplatinum chemotherapy in patients with platinum-sensitive recurrent disease with germline BRCA mutations. Clinical trials are ongoing or planned to specifically address how PARP inhibitors will fit into the treatment paradigm for ovarian cancer. Our hope is that PARP inhibitors, either as single agents or in combination regimens, might actually replace chemotherapy in a situation where chemotherapy is the current standard of care. More new data on PARP inhibitors in ovarian cancer are eagerly awaited.

Your Thoughts
What are your thoughts on using PARP inhibitors in patients with platinum-sensitive recurrent ovarian cancer? I encourage you to answer the polling question and post your thoughts in the comments box below.