First-Line Rucaparib Maintenance Provides Long-Term Benefits in Newly Diagnosed Ovarian Cancer

Rebecca Kristeleit, BSc, MBChB, MRCP, PhD

In addition to providing a progression-free survival (PFS) benefit vs placebo, rucaparib (Rubraca) maintenance therapy was found to prolong both time to first subsequent treatment (TFST) and second disease progression or death (PFS2) in patients with newly diagnosed ovarian cancer regardless of homologous recombination deficiency (HRD) or BRCA mutation status, according to Rebecca Kristeleit, BSc, MBChB, MRCP, PhD.¹

Updated results from the long-term analysis of the ATHENA-MONO portion of the phase 3 ATHENA study (NCT03522246) were presented during the 2024 SGO Annual Meeting on Women’s Cancer. In the intention-to-treat (ITT) population, the median TFST for patients treated with rucaparib (n = 427) was 23.3 months (95% CI, 19.3-26.8) vs 12.1 months (95% CI, 10.1-16.1) in those treated with placebo (n = 111; HR, 0.52; 95% CI, 0.40-0.67) after a median follow-up of 37.1 months. The median PFS2 was 36.0 months (95% CI, 29.5-44.6) and 26.8 months (95% CI, 21.7-not reached [NR]) with rucaparib and placebo, respectively (HR, 0.84; 95% CI, 0.63-1.13).

Among those in the HRD population, the median TFST was 32.7 months (95% CI, 26.0-NR) with rucaparib (n = 185) vs 15.1 months (95% CI, 10.3-13.7) with placebo (n = 49; HR, 0.50; 95% CI, 0.33-0.76). The median PFS2 was NR (95% CI, 39.0-NR) in the rucaparib arm and was 39.9 months (95% CI, 24.2-NR) in the placebo arm (HR, 0.75; 95% CI, 0.46-1.24). Overall survival (OS) data were not mature at the time of this analysis.

Findings from ATHENA-MONO supported the approval of rucaparib by the European Commission as first-line maintenance for patients with advanced ovarian cancer who have responded following the completion of frontline platinum-based chemotherapy.²

“The long-term end points that were presented from the ATHENA-MONO study strengthen the use of rucaparib in the first-line [maintenance] setting as an additional drug that works irrespective of molecular status and with a very manageable toxicity profile,” said Kristeleit, who serves as a consultant medical oncologist for Guy’s and St Thomas’ NHS Foundation Trust and NIHR Guy’s Clinical Research Facility, in London, United Kingdom. “That can only be good news for women.”

In an interview with OncLive^®, Kristeleit discussed the rationale behind the ATHENA-MONO trial, expanded on post-progression data with rucaparib and their implications for clinical practice, and emphasized the evolving landscape of research in gynecologic oncology.

OncLive: What was the rationale for evaluating the efficacy of first-line rucaparib maintenance therapy according to HRD or BRCA status in the ATHENA-MONO trial?

Kristeleit: We’ve seen previously and hypothesized that maintenance treatment in women with advanced ovarian cancer who achieved a complete or partial response following first-line treatment with a combination of surgery and chemotherapy have better survival outcomes. Previous data have suggested and shown that these survival outcomes vary according to molecular status. We’ve seen that with other PARP inhibitors in the first-line setting and also with rucaparib in the recurrent setting.

The aim of the ATHENA-MONO study was to establish whether women with advanced ovarian cancer treated with surgery and chemotherapy [who experienced a] complete or partial response would benefit from [first-line] rucaparib as maintenance [therapy] for up to 2 years. We thought this [benefit] was likely to [occur] irrespective of any HRD or BRCA status. That’s what we wanted to establish.

The long-term follow-up analysis that we presented [at this year’s SGO Annual Meeting] looked at TFST, PFS2, and OS. This was an ad-hoc analysis that was completed predominantly to support an application to the European Medicines Agency to get approval for the use of rucaparib in the first-line setting.

What key efficacy findings from this follow-up analysis were presented at the meeting?

The key efficacy findings from this 3-year follow-up [study] of patients within the ATHENA-MONO study showed that the clinical benefit of rucaparib extended beyond first progression and beyond the 2-year completion of treatment. Compared with placebo, we’re seeing a [prolongation to] TFST and PFS2 [with first-line rucaparib maintenance]. Giving rucaparib in the first-line setting is actually [allowing] women to maintain benefit through, and following, their second-line treatment. This is a reassuring and important finding.

Additionally, OS data were immature in this report. It was 35% mature in the ITT population and 25% mature in the HRD population. However, we are seeing a trend toward improved OS. The hazard ratios are less than 1 in both primary analysis populations. Although the median OS was not reached for either of the rucaparib arms, or the placebo arm for the HRD group, it was reached for the placebo arm in the ITT population. [With] OS, separation of the curves is happening at approximately 30 months. It is reassuring that we’re beginning to see signals of potential OS benefit with the use of rucaparib as a first-line treatment.

What toxicities were observed with frontline rucaparib in this trial?

Rucaparib has been quite intensively investigated already as a maintenance treatment in the recurrent setting. Compared with [safety] findings in the recurrent setting, we’re not seeing any new signals with the use of rucaparib in the first-line setting. As with all PARP inhibitors, we do see some patients developing myelodysplastic syndrome and acute myeloid leukemia, but compared with placebo there doesn’t appear to be a significant difference [in the incidence of these malignancies.] The toxicity profile is very manageable.

What are the clinical implications of these long-term findings for patients with newly diagnosed ovarian cancer?

This analysis was done to support an approval in Europe for the use of rucaparib in the first-line setting and that approval is now in place. As results continue to mature, more long-term data will be coming out. The data cutoff [date was] March 9, 2023, so more long-term data will be presented relatively soon. I’m hoping that these data will help support further approvals, hopefully in the United States.

What future directions do you foresee for research in gynecologic oncology?

[We are] beginning to [identify these] molecular groups within gynecological cancer that may be started with PARP inhibitors and understand that there can be differences in benefit according to molecular status, [although] benefit [can still be achieved] across a wide range [of subgroups]. We’re seeing this play out in terms of new drug classes, such as antibody-drug conjugates or folate receptor alpha–targeted drugs, and it looks like we’ll be targeting HER2-expressing cancers with some of these drugs. This is beginning to help us optimize benefit for women. We’re also seeing certain benefits with drugs in histological subtypes such as low-grade serous ovarian cancer. This is a massive step forward. It represents a change in thinking and management [approaches] across gynecological cancers. It’s important and is changing our approach to how we manage patients in a very informed way.

References

1. Kristeleit RS, O’Malley DM, Lim, MC, et al. Interim post-progression data and updated survival in patients with newly diagnosed advanced ovarian cancer in ATHENA-MONO. Presented at the 2024 SGO Annual Meeting on Women’s Cancer; San Diego, CA; March 16-18, 2024.
2. European Commission approves pharmaand GmbH’s Rubraca (rucaparib) as a first-line maintenance treatment in advanced ovarian cancer. News Release. Pharmaand GmbH. November 20, 2023. Accessed April 9, 2024. https://www.pharmaand.com/wp-content/uploads/2023/11/Rubraca-1st-line-aOC-EC-Decision-News-Release.pdf