Clovis Oncology is already fighting the FDA over expanding Rubraca into an earlier treatment line in ovarian cancer. Now, the company hopes the U.S. regulator could allow the troubled PARP inhibitor a similar move in prostate cancer—but the situation is complicated.
Rubraca cut the risk of tumor progression or death by 39% versus chemotherapy or second-line androgen deprivation therapy in patients with metastatic castration-resistant prostate cancer (mCRPC) with mutations in BRCA or ATM, Clovis said Monday.
The phase 3 TRITON3 trial serves as the confirmatory study for Rubraca’s FDA accelerated approval for BRCA-mutated mCRPC in patients who’ve received an androgen receptor blocker and a taxane-based chemotherapy. Now, Clovis hopes to convert that nod, granted in 2020, into a full approval and expand Rubraca to mCRPC patients who have not received chemo. But there’s a catch.
Clovis said it plans to file an application in the BRCA subgroup in the first quarter of 2023 but “intends to discuss with the FDA” about the broader population. That’s because of a lack of showing in the ATM subgroup.
In TRITON3, Rubraca’s benefit in slowing disease progression appeared to be primarily driven by the BRCA-mutated group. There, the drug significantly cut the risk of progression or death by 50%. Patients on Rubraca lived a median 11.2 months, versus 6.4 months in the control group, which received physician’s choice of treatment including the chemotherapy docetaxel or a next-generation androgen receptor-targeted therapy of either Johnson & Johnson’s Zytiga or Pfizer and Astellas’ Xtandi.
But when it comes to an exploratory analysis in the ATM group, the drug showed almost no risk reduction. Patients in the Rubraca arm went 8.1 months without progression, versus 6.8 months in the control group. To make things worse, mature data on patient survival actually favored the control arm among the ATM patients. Overall survival in the BRCA subgroup wasn’t mature but favored Rubraca at the interim analysis.
Before Rubraca’s latest data, AstraZeneca and Merck’s PARP inhibitor Lynparza had in 2020 won an FDA go-ahead for a broader population of previously treated mCRPC patients with any homologous recombination repair (HRR) gene mutation who have progressed after Zytiga or Xtandi.
In its own PROfound trial, Lynparza also failed to show a progression-free survival benefit in the ATM subgroup when compared with either Xtandi or Zytiga. But in an exploratory analysis, the PROfound trial investigators noted that Lynparza appeared to perform worse in patients without prior taxane treatment—the same population targeted in Rubraca’s current TRITON3 trial—but could confer a benefit in those with taxane experience.
With TRITON3, Rubraca is the first PAPR to show superior progression-free survival over a control arm that includes chemotherapy, which is today the standard of care for these second-line mCRPC patients, Clovis CEO Patrick Mahaffy said in a Monday statement.
Rubraca’s latest mCRPC data come on the heels of Clovis requesting the FDA to approve the PARP inhibitor as a first-line maintenance treatment for ovarian cancer patients who have responded to a round of chemotherapy. The company filed the application despite the FDA’s demand for more mature patient survival data.
The FDA has raised concern about PARP inhibitor class of drugs’ potential detrimental effects on long-term patient survival in late-line ovarian cancer treatment despite a clear tumor progression benefit. Rubraca, Lynparza and GSK’s Zejula have recently all withdrawn their late-line ovarian cancer indications in the U.S.
Whether that regulatory concern extends to Rubraca in mCRPC remains to be seen. Lynparza in the PROfound trial demonstrated a statistically significant overall survival advantage versus Zytiga or Xtandi for the subgroup of patients with BRCA or ATM mutations.