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Rubraca sheds positive light for PARP inhibitors in endometrial cancer

On 18 March 2024, positive Phase II results of Clovis Oncology’s Rubraca were presented at the Society of Gynecologic Oncology conference, where Rubraca was evaluated as maintenance therapy in patients with metastatic and recurrent endometrial cancer, following one or two prior lines of systemic therapy.

The key unmet need in endometrial cancer is the high rate of recurrence and the subsequent lack of approved maintenance therapies, opening a door for Rubraca to be the first polyadenosine diphosphate-ribose polymerase (PARP) inhibitor to infiltrate this space following confirmatory studies and potentially paving the way for other PARP inhibitors, including AstraZeneca’s Lynparza and GlaxoSmithKline’s Zejula.

Rubraca belongs to a class of drugs that inhibit PARP, preventing the repair of single-strand DNA breaks and leading to cancer cell death.

PARP inhibitors have shown significant benefits in ovarian cancer treatment, particularly for patients harbouring a germline mutation of the breast cancer gene 1/2 and homologous repair deficiency-related genes.

Therefore, the Phase II results of Rubraca to translate the success seen in ovarian cancer to endometrial cancer are encouraging.

The results demonstrate that Rubraca was well-tolerated and had met its primary endpoint with a statistically significant extended median progression-free survival (PFS) compared with placebo (28.1 vs. 8.7 months).

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Although the trial did not meet the overall survival endpoint, the results represent a clear clinical benefit for these patients.

While cross-trial comparisons should proceed with caution, the similar Phase IIb UTOLA trial evaluating Lynparza as maintenance following platinum-based chemotherapy failed to exhibit a significant PFS, which set a precedent for PARP inhibitors in endometrial cancer.

However, this outcome may have been impacted by patient eligibility criteria, for example, the exclusion of patients with stable disease, and differences in PARP trapping among PARP inhibitors.

The potential synergy between PARP and immune checkpoint inhibitors (ICIs) has been observed in past clinical trials, providing a novel combination strategy for endometrial cancer patients.

The Phase III DUO-E trial demonstrated that the combination of AstraZeneca’s Imfinzi and Lynparza as maintenance following chemotherapy with Imfinzi conferred a reduced risk of disease progression by 45%.

Additionally, the Phase III RUBY Part 2 trial investigating GSK’s ICI Jemperli in combination with chemotherapy and as maintenance in combination with the PARP inhibitor Zejula showed a similar improvement that significantly reduced the risk of disease progression or death by 40%, and improved median PFS by 6.2 months.

Rubraca’s sales across the seven major markets (the US, France, Germany, Italy, Spain, UK, and Japan) are predicted to reach $243m by 2030, according to GlobalData’s patient-based ovarian cancer forecast.

Although these sales may increase with potential approval in endometrial cancer, the recent voluntary withdrawals within ovarian cancer and patent expiries occurring within the next ten years will negatively impact sales.