The Role of Rucaparib in Ovarian Cancer Following the ARIEL4 Readout

Amit M. Oza, MD

Among patients with advanced, relapsed ovarian carcinoma and a deleterious BRCA 1/2 mutation, rucaparib (Rubraca) did not show an improvement in progression-free survival (PFS) at next line of therapy (PFS2). Moreover, overall survival (OS) was similar between the treatment arms, according to findings from the ARIEL4 trial (NCT02855944).¹

ARIEL4 investigators led by Amit M. Oza, MD discovered previously that there is a PFS advantage with rucaparib in comparison with chemotherapy. Results published in the Lancet Oncology earlier in 2022 show a median PFS of 7.4 months (95% CI, 6.7-7.9) with rucaparib vs 5.7 months (95% CI, 5.5-6.7) with chemotherapy (HR, 0.67; 95% CI, 0.52-0.86; P = .0017), in the overall population.²

OS results from 349 patients were presented during the European Society of Medical Oncology (ESMO) Congress 2022. In the intention-to-treat (ITT) population, the median OS was 19.4 months (15.2-23.6) in the rucaparib arm compared with 25.4 months (95% CI, 21.4-27.6) in the chemotherapy group (HR, 1.313; 95% CI, 0.999-1.725).¹

According to Oza, a senior scientist in the Princess Margaret Cancer Centre Cancer Clinical Research Unit at Princess Margaret Cancer Centre and co-leader of the Ovarian Cancer Translational Research Initiative at the Ontario Institute for Cancer Research, the difference in OS was caused by the subgroup of patients with platinum-resistant disease. In this subgroup, the median OS was 14.2 months (95% CI, 11.8-17.4) in the rucaparib group vs 22.2 months (95% CI, 15.4-26.2) in the chemotherapy group (HR, 1.511; 95% CI, 1.053-2.170). Among the patients with platinum sensitivity, the median OS was 29.4 months (95% CI, 23.1-37.4) in those treated with rucaparib compared with 27.6 months (95% CI, 21.9-47.2) in the chemotherapy group (HR, 1.071; 95% CI, 0.709-1.618).

The OS analysis did not reveal any new safety signals. Adverse events (AEs) of special interest were the occurrence of myelodysplastic syndrome or acute myeloid leukemia, which occurred in in 3% of patients (3%) in the rucaparib arm compared with 0 in the chemotherapy arm.

In an interview with Targeted Oncology™, Oza, discussed the OS analysis of the ARIEL4 clinical trial and unanswered questions about rucaparib treatment in certain ovarian cancer subgroup populations.

TARGETED ONCOLOGY: Can you talk about the role of rucaparib in ovarian cancer based on previous clinical trials?

Oza: Rucaparib is a PARP inhibitor that’s been used in multiple different clinical trials. It shows good evidence of activity, similar in terms of its magnitude to other PARP inhibitors. What has been shown previously is that rucaparib is effective in maintenance setting of platinum-sensitive, recurrent disease. It improves progression-free survival, and when given as a maintenance therapy, there's also some tantalizing evidence that will emerge related to rucaparib’s role in a first-line setting.

In terms of its overall activity, the magnitude seems to be very similar to level of activity seen with olaparib [Lynparza] or niraparib [Zejula]. Its safety profile is good, and it's a drug that has been well tolerated. Generally, it's an active agent. The study that I presented on at ESMO looked at rucaparib’s role in a recurrent setting in both platinum-resistant and platinum-sensitive disease.

Can you discuss the data previously reported from the ARIEL4 study?

The previous studies have been looking at early phase studies followed by randomized studies that have examined its role in the maintenance setting. In ARIEL4, we were looking at patients with a deleterious BRCA1/BRCA2 mutation, and then looking at the role of single-agent rucaparib in treating recurrent disease. There were 3 different types of patients that were identified. These included patients that are fully platinum-sensitive, patients who are in partially platinum-sensitive, and then patients who are deemed to be platinum-resistant.

In this study, rucaparib was compared head-to-head with platinum-based chemotherapy in platinum-sensitive patients. The progression-free survival results were presented about 18 months to 2 years ago, which really showed that there was an improvement in progression-free survival in the intent-to-treat population as well as the subgroups.

What findings did you present recently at the ESMO Congress 2022?

This analysis was dealing with was the overall survival results to see the impact of rucaparib in terms of overall survival in the intent-to-treat population. It was preplanned as a secondary analysis. What the results show was that the chemotherapy patients seem to do better. The overall hazard ratio was 1.3, but when you drill down at the results carefully, it shows that patients who are platinum-resistant are the ones that are driving that survival advantage for chemotherapy compared with rucaparib. Patients who are platinum sensitive, had no overall survival difference in terms of their treatment.

Overall survival is challenging end point because of post-progression treatment, and progression treatment was a very important facet of this study. When we look at peak progression-free survival to which is the next line of treatment, we see that there was no adverse impact in platinum-resistant disease. In terms of platinum-sensitive disease, there was still a continued advantage of giving rucaparib. There was also a crossover that was preplanned and built into the study, which was progression treatment. What we saw was that overall, 90% of the patients ended up having rucaparib. The patients who crossed over to rucaparib did quite well in all 3 groups. There was 1 other facet that we are still drilling down on to try and get further explanation iand it is that about 40% of the patients that were on the rucaparib arm did not receive post-progression treatment of any kind. That is a little bit surprising and it's not clear what that is related to. We will need to dig down into that part of the result.

What questions linger after this analysis?

One of the intriguing components is from the translational analysis and what we had initially done in the PFS analysis is look at resistance mechanisms that develop that would make it less likely for patients to benefit from PARP. One of the resistance mechanisms that develops is reversion mutations, and we have seen at the outset that if you take patients who have reversion mutations, they do better with chemotherapy compared with rucaparib. What we have also seen is that in the platinum-resistant patient population, we found about 4 patients where there was a sequential analysis done in terms of the level of reversion mutations that are present. When we look at the level of revision mutations that were identified, there seemed to be a driving down of the in terms of the frequency of revision mutations in 3 out of those 4 patients with weekly paclitaxel. What's intriguing is that perhaps reversion mutation, which represent a clone of disease in the patient, can be reduced. I think it's an intriguing observation that we need to further develop in terms of identifying mechanisms of resistance upfront. Then, how do we deal with them?

I think it also is very clear that if you have a patient with platinum-resistant disease, then in those patients, it is probably better to give them treatment with chemotherapy sequentially. I think what is also important is to really look at the sequential treatments following rucaparib and identify what are the sort of things that we can learn in terms of those patients benefit to treat and subsequently, and there's some still lingering questions as to why 40% of the patients did not have post-progression treatment when they were randomized to rucaparib.

_REFERENCES:

_{1. Oza AM, Lisyanskaya AS, Fedenko AA, et al. Overall survival results from ARIEL4: A phase III study assessing rucaparib vs chemotherapy in patients with advanced, relapsed ovarian carcinoma and a deleterious BRCA1/2 mutation. Ann Oncol. 2022;33(suppl 7): 518O. doi:10.1016/annonc/annonc1054}

_{2. Kristeleit R, Lisyanskaya A, Fedenko A, et al. Rucaparib versus standard-of-care chemotherapy in patients with relapsed ovarian cancer and a deleterious BRCA1 or BRCA2 mutation (ARIEL4): an international, open-label, randomised, phase 3 trial. Lancet Oncol. 2022;23(4):465-478. doi:10.1016/S1470-2045(22)00122-X}