Dr Kristeleit on the Implications of Long-Term Data With Rucaparib in Advanced Ovarian Cancer

Rebecca Kristeleit, BSc, MBChB, MRCP, PhD, consultant medical oncologist, clinical senior lecturer, Department of Oncology, University College-London Cancer Institute, discusses the phase 3 ATHENA-MONO trial (NCT03522246) in newly diagnosed patients with advanced ovarian cancer, highlighting the clinical implications of these long-term findings.

unveiled a comprehensive follow-up analysis

 examining key end points, such as time to first subsequent treatment (TFST), second disease progression or death (PFS2), and overall survival. The primary motivation behind conducting this ad-hoc analysis was to furnish essential data in support of an application submitted to the European Medicines Agency seeking the European approval for the use of rucaparib (Rubraca) in the first-line ovarian cancer setting, a milestone that has since been successfully achieved, Kristeleit begins.

As the findings continue to evolve and mature, Kristeleit says she and investigators anticipate the release of additional long-term data. The cutoff date for the data stands at March 9, 2023, indicating that further insights into the long-term efficacy of rucaparib will be forthcoming in the near future, Kristeleit notes. Kristeleit goes on to share that her optimism rests on the belief that these data will not only fortify existing rucaparib approvals but also pave the way for potential approvals of this agent within the United States.

The long-term outcomes delineated in the ATHENA-MONO study serve to underscore the efficacy of rucaparib in the first-line maintenance setting as an adjunctive therapy, independent of molecular status, and characterized by a notably manageable toxicity profile, she continues. This development heralds positive implications for women grappling with ovarian cancer, Kristeleit adds. Apart from yielding a progression-free survival advantage over placebo, rucaparib maintenance therapy has demonstrated efficacy in prolonging both TFST and PFS2 in patients newly diagnosed with ovarian cancer, irrespective of homologous recombination deficiency or 

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Rebecca Kristeleit, BSc, MBChB, MRCP, PhD, discusses the ATHENA-MONO trial in newly diagnosed patients with advanced ovarian cancer.

Dr Kristeleit on the ATHENA-MONO Trial in Ovarian Cancer

Rebecca Kristeleit, BSc, MBChB, MRCP, PhD, consultant medical oncologist, clinical senior lecturer, Department of Oncology, University College-London Cancer Institute, discusses the rationale for conducting the phase 3 ATHENA-MONO trial (NCT03522246) in newly diagnosed patients with advanced ovarian cancer, highlighting the implications of the 3-year follow-up data derived from the study.

Previous observations and hypotheses have indicated that maintenance therapy may confer survival benefits to women with advanced ovarian cancer who achieve a complete or partial response following first-line treatment comprising surgery and chemotherapy, Kristeleit begins. Notably, data from various studies have indicated that these survival outcomes can vary based on molecular status, as demonstrated with other PARP inhibitors, including rucaparib (Rubraca), in both the first-line and recurrent settings, she states. The ATHENA-MONO study evaluated whether women with advanced ovarian cancer would derive benefit from receiving rucaparib maintenance therapy for up to 2 years, Kristeleit adds. The study investigated this potential benefit with rucaparib maintenance therapy irrespective of homologous recombination deficiency or 

 mutation status to reveal the treatment’s efficacy in a broad patient population, according to Kristeleit.

presented the results of a long-term follow-up analysis

 of ATHENA-MONO focusing on time to first subsequent therapy, second progression-free survival, and overall survival outcomes, Kristeleit reports. This ad-hoc analysis primarily supported an application to the European Medicines Agency seeking approval for the first-line use of rucaparib in patients with advanced ovarian cancer.

Questions have arisen regarding the toxicities associated with frontline rucaparib in this trial, she continues. Notably, rucaparib has undergone extensive investigation as a maintenance therapy in the recurrent setting, Kristeleit notes. Comparatively, the safety findings observed in the first-line setting revealed no new safety signals, Kristeleit elucidates. Although the incidence of myelodysplastic syndrome and acute myeloid leukemia with rucaparib were consistent with the class effect of PARP inhibitors, there was no significant difference in the incidence of these secondary hematologic malignancies in the rucaparib arm compared with the placebo group, Kristeleit says. Overall, the toxicity profile of rucaparib was deemed manageable, offering reassurance regarding its safety as a first-line treatment for patients with advanced ovarian cancer, she concludes.

Rebecca Kristeleit, BSc, MBChB, MRCP, PhD, discusses the phase 3 ATHENA-MONO trial in newly diagnosed patients with advanced ovarian cancer.

Dr Kristeleit on 3-Year Follow-up Data for Rucaparib Maintenance in Ovarian Cancer

Rebecca Kristeleit, BSc, MBChB, MRCP, PhD, consultant medical oncologist and clinical senior lecturer, University College-London Cancer Institute, discusses key efficacy outcomes derived from 3-year follow-up data from newly diagnosed patients with advanced ovarian cancer treated in the phase 3 ATHENA-MONO trial (NCT01968213).

Findings presented at the 2024 SGO Annual Meeting on Women’s Cancer demonstrated that time to first subsequent therapy (TFST) and time to second progression (PFS2) data pointed to a continued benefit for single-agent rucaparib (Rubraca) compared with placebo.

Patients in the intent-to-treat (ITT) population treated with rucaparib plus a placebo for nivolumab (Opdivo; n = 427) experienced a median TFST of 23.3 months (95% CI, 19.3-26.8) compared with 12.1 months (95% CI, 10.1-16.1) for those given dual placebos (n = 111; HR, 0.52; 95% CI, 0.40-0.67). In patients with homologous recombination deficiency (HRD), the median TFST was 32.7 months (95% CI, 26.0–not reached [NR]) for the rucaparib arm (n = 185) vs 15.1 months (95% CI, 10.3-31.7) for the dual placebo arm (n = 49; HR, 0.50; 95% CI, 0.33-31.7).

Additionally, patients in the ITT population given rucaparib achieved a median PFS2 of 36.0 months (95% CI, 29.5-44.6) compared with 26.8 months (95% CI, 21.7-NR) for those given placebo. In the HRD-positive population, the median PFS2 was NR (95% CI, 39.0-NR) and 39.9 months (95% CI, 24.2-NR), respectively.

Based on these data, the clinical advantages of rucaparib persist beyond progression of ovarian cancer and completion of the two-year treatment course, Kristeleit says. Furthermore, Kristeleit explains that although overall survival (OS) data remain premature, a noteworthy trend favoring rucaparib has been observed. At data cutoff, OS data were at 35% maturity for the ITT population and 25% maturity for the HRD population.

These TFST and PFS2 findings extend the understanding of rucaparib's therapeutic benefits, positioning it as a viable option for maintenance therapy following first-line treatment in patients with advanced ovarian cancer, Kristeleit continues. The sustained efficacy of rucaparib in prolonging progression-free intervals suggests its utility in delaying disease progression and potentially improving long-term outcomes in this patient population, she adds.

These findings have significant clinical implications, suggesting that rucaparib may confer a survival benefit when used as first-line therapy in patients with ovarian cancer, Kristeleit adds. Further follow-up and analysis are warranted to validate these preliminary findings and elucidate the full extent of rucaparib's efficacy and safety profile in this patient population, she concludes.

Rebecca Kristeleit, BSc, MBChB, MRCP, PhD, on efficacy outcomes from the 3-year follow-up for patients with advanced ovarian cancer in the ATHENA-MONO study.

Rebecca Kristeleit, BSc, MBChB, MRCP, PhD, clinical senior lecturer and a consultant medical oncologist at the University College-London Cancer Institute, discusses the importance of patient-reported outcomes (PROs) in the phase 1 GARNET trial in advanced or recurrent mismatch repair deficient/microsatelite instability-high endometrial cancer.

PROs were completed for 66 of the 104 patients included in the GARNET study, says Kristeleit. The PROs indicated that dostarlimab (formerly TSR-042) was very well tolerated. In fact, 37% of patients reported improved scores, so the agent led to an improvement in quality of life (QoL) for some patients, Kristeleit says.

These PRO scores are very important, not only to understand and capture the effect of this drug on patients, but it is a factor acknowledged by regulators and licensing bodies as a very important component of licensing these drugs. Additionally, these PROs help promote understanding not just of the numerical or statistical findings that are being measured, such as response rate and duration of response, but also what that means for the patient taking the drug, explains Kristeleit. The drug was found to be very tolerable by patients; they have to take the agent for a long period of time and many experienced improved QoL while on dostarlimab, concludes Kristeleit.

Rebecca Kristeleit, BSc, MBChB, MRCP, PhD, discusses the importance of patient-reported outcomes in the phase 1 GARNET trial in advanced or recurrent mismatch repair deficient/microsatelite instability-high endometrial cancer.

Dr. Kristeleit on QoL With Dostarlimab in dMMR/MSI-H Endometrial Cancer

Rebecca Kristeleit, BSc, PhD, consultant medical oncologist, University College-London Cancer Institute, discusses the safety profile of rucaparib in the treatment of patients with ovarian cancer.

These safety data come from an analysis of 2 phase II trials that looked at heavily pretreated patients with high-grade ovarian cancer and germline or somatic 

 mutations who showed a durable response to rucaparib. According to Kristeleit, the agent demonstrated side effects that were very consistent with those seen in the use of other PARP inhibitors. The dominant side effects included fatigue, nausea, and anemia.

Dose interruptions and dose reductions were very effective methods to manage these adverse events, she says. Of the 377 patients included in the safety assessment in this study, only 8% discontinued due to treatment-related adverse events. These data indicate that, although dose adjustments may be required for some patients, many are able to continue with rucaparib for the long-term.

Dr. Kristeleit on the Safety Profile of Rucaparib in Ovarian Cancer

Rebecca Kristeleit, BSc, PhD, consultant medical oncologist, University College-London Cancer Institute, discusses the efficacy of rucaparib in the treatment of patients with ovarian cancer.

According to the results of an analysis of 2 phase II trials presented at the 2016 ESMO Congress, the majority of heavily pretreated patients with high-grade ovarian cancer and germline or somatic 

 mutations showed a durable response to rucaparib.

Kristeleit explains that the radiological cutoff for identifying which patients "respond" is determined by tumor shrinkage of at least 30%. However, she says, there were still patients in this analysis whose tumors shrunk by approximately 28% or 29%, and while they do not necessarily meet the specified cutoff, it is important to note that these individuals are still benefiting from the treatment in a significant way.

Moreover, at 6 months, 79% of patients were progression-free, according to Kristeleit. At 12 months, that number was still over 40%, and at nearly 2 years, approximately 10% of women still had not progressed. This is exciting data, particularly for this heavily pretreated, relatively platinum-sensitive patient population.

Rebecca Kristeleit, BSc, PhD

Articles

Dr Kristeleit on the Implications of Long-Term Data With Rucaparib in Advanced Ovarian Cancer

Dr Kristeleit on the ATHENA-MONO Trial in Ovarian Cancer

Dr Kristeleit on 3-Year Follow-up Data for Rucaparib Maintenance in Ovarian Cancer

Dr. Kristeleit on QoL With Dostarlimab in dMMR/MSI-H Endometrial Cancer

Dr. Kristeleit on the Safety Profile of Rucaparib in Ovarian Cancer

Dr. Kristeleit on the Efficacy of Rucaparib in Ovarian Cancer