TRITON3 Phase 3 Trial Of Rubraca® (Rucaparib) Achieves Primary Endpoint In Men With Metastatic Castration-Resistant Prostate Cancer With BRCA or ATM Mutations

  • TRITON3 study evaluating Rubraca monotherapy versus chemotherapy or second-line androgen deprivation therapy in patients with metastatic castration-resistant prostate cancer (mCRPC) with mutations in BRCA or ATM achieved the primary endpoint of improved radiographic progression-free survival (rPFS) by independent radiology review (IRR)
    • Median rPFS of 11.2 months for Rubraca vs 6.4 months for control group in the BRCA subgroup – Median rPFS of 10.2 months for Rubraca vs 6.4 months for control group in the ITT population (inclusive of all patients with a BRCA or ATM mutation enrolled in TRITON3)
  • Safety profile of Rubraca observed in TRITON3 was consistent with Rubraca labelling
  • TRITON3 is the confirmatory study for Rubraca’s current US accelerated approval in mCRPC and will also serve as the basis of a supplemental New Drug Application (sNDA) for US label expansion to be submitted during Q1 2023
  • TRITON3 data have been submitted for presentation at the Prostate Cancer Foundation Annual Scientific Retreat later this month and will also be submitted for presentation at a 2023 medical meeting
Reno, Nevada (UroToday.com) -- Clovis Oncology, Inc. announced positive top-line data from the Phase 3, open-label, multicenter, randomized TRITON3 trial demonstrating that Rubraca monotherapy treatment achieved the primary endpoint of significantly improved radiographic progression-free survival (rPFS) by independent radiology review (IRR) compared with the control group, which consisted of physician’s choice of docetaxel, abiraterone acetate, or enzalutamide. Benefit was observed in both primary efficacy analyses of patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC): first, those who had mutations in BRCA, as well as all patients randomized in the trial, inclusive of mutations in BRCA or ATM (the overall intent-to-treat population (ITT)). The safety profile of Rubraca observed in the TRITON3 study was consistent with Rubraca labelling.


During the first quarter of 2023, the Company plans to submit a supplemental New Drug Application (sNDA) to the FDA for the BRCA subgroup of patients and intends to discuss with the FDA submitting for the broader ITT population.

“We believe that the positive results from TRITON3 further demonstrate the important role that Rubraca can play as a treatment option for men with metastatic castration-resistant prostate cancer associated with homologous recombination deficiency, and we look forward to submitting these data to the regulatory authorities in the US during Q1 2023. Not only does this provide a potential treatment option for eligible men with earlier stage disease, but it is the first and only PARP inhibitor that has demonstrated superior radiographic PFS compared to chemotherapy, which is today the standard of care for these patients,” said Patrick J. Mahaffy, President and CEO of Clovis Oncology. “Most importantly, I would like to thank the patients, physicians, and our colleagues whose commitment to this trial made these results possible, which now offer the potential to make a difference in the lives of many men with advanced prostate cancer.”

“Men with this type of metastatic prostate cancer want to get their genetically targeted therapy as early as possible, and this trial clearly shows the value of rucaparib as a treatment for these men,” said Alan H. Bryce, MD, chair of the Division of Hematology and Medical Oncology at the Mayo Clinic and principal investigator of the TRITON3 trial. “A key point is that rucaparib can replace chemotherapy in this setting. The current standard of care for these men is chemotherapy with docetaxel, and rucaparib is the only PARP inhibitor which has beaten a docetaxel-containing control arm in a clinical trial.”

“This trial demonstrates the potential for rucaparib to treat men with early-stage metastatic castration-resistant prostate cancer,” said Karim Fizazi, MD, PhD, medical oncologist at Gustave Roussy, and a full professor in Oncology at the University of Paris-Saclay and principal investigator of the TRITON3 trial. “To my knowledge, this is the first time in two decades that a potential new treatment, rucaparib, has shown in a randomized controlled trial radiographic PFS efficacy over an investigator’s choice control arm that included docetaxel chemotherapy, a long-standing standard of care for men with metastatic castration-resistant prostate cancer, and this is excellent news for patients.”

TRITON3 is a Phase 3, multicenter, open-label, randomized trial of Rubraca in patients with chemotherapy-naïve mCRPC. The study enrolled 405 patients with a mutation in BRCA or ATM who were randomized to Rubraca or the control group, which consisted of physician’s choice of docetaxel, abiraterone acetate, or enzalutamide. Approximately 55% of the patients in the control arm received docetaxel. The primary endpoint was rPFS by IRR, in patients with mutations in BRCA1, BRCA2or ATM. TRITON3 was designed as a Phase 3 trial to confirm and expand the efficacy data from TRITON2 in an earlier treatment setting against a relevant control arm.

Patients were required to have disease progression after treatment with one prior next-generation AR-targeted therapy (abiraterone acetate, enzalutamide, apalutamide or investigational agent), as well as a deleterious mutation in BRCA or ATM. Following a protocol amendment, patients were permitted to have received a qualifying AR-targeted therapy in either the hormone-sensitive or castration-resistant setting, and as a result, approximately 18% of patients in TRITON3 had received prior AR-targeted therapy in the metastatic hormone-sensitive setting only.

The primary efficacy analysis evaluated two prospectively defined molecular sub-groups in a step-down manner: 1) the BRCA subgroup, and 2) all patients randomized (ITT) in TRITON3, inclusive of those with BRCA or ATM mutations.

Following is a summary of the primary efficacy analyses of rPFS by independent radiologic review (IRR), the primary analysis of TRITON3.

Significant Improvement in rPFS in the BRCA Patient Population

The Rubraca arm (n=201) achieved statistical significance over the control arm (n=101) for the primary endpoint of rPFS with a hazard ratio of 0.50 (95% CI: 0.36-0.69). The median PFS for the population of patients with BRCA mutations treated with Rubraca was 11.2 months vs 6.4 months among those who received physician’s choice (p<0.0001).

Significant Improvement in rPFS in the ITT population, inclusive of those with BRCA or ATM mutations

Rubraca also showed statistical significance in all 405 patients randomized in TRITON3. The Rubraca arm (n=270) successfully achieved statistical significance over the control arm (n=135) for the primary endpoint of rPFS with a hazard ratio of 0.61 (95% CI: 0.47-0.80). The median PFS for all patients enrolled in TRITON3 and treated with Rubraca was 10.2 months vs 6.4 months among those who received physician’s choice (p=0.0003).

rPFS in Exploratory ATM Mutation Subgroup

In the exploratory subgroup of men with tumor ATM mutations (n=103), the hazard ratio for rPFS was 0.97 (95% CI: 0.59-1.52). Median rPFS in the Rubraca arm (n=69) was 8.1 months vs 6.8 months in the control arm (n=34) with a nominal p-value (p=0.8421).

Secondary Endpoint of Overall Survival Summary

The hazard ratio for the interim analysis of the secondary endpoint of overall survival (OS) in the BRCA subgroup and ITT population, which are not yet mature, favored Rubraca. The hazard ratio for OS in the exploratory subgroup of ATM, which is mature, favored the control arm. The 95% confidence intervals for these OS analyses included less than one for the exploratory endpoint ATM, signifying no statistical difference in outcomes between Rubraca and control.

Summary of TRITON3 Safety

The safety profile of Rubraca observed in TRITON3 was consistent with Rubraca labelling.The most common (≥5%) treatment-emergent grade 3 or higher adverse events (TEAEs) among all patients treated with Rubraca in the TRITON3 study were anemia/decreased hemoglobin (23.7%), neutropenia/decreased neutrophil count (7.4%), asthenia/fatigue (7.0%), thrombocytopenia/decreased platelet count (5.9%) and increased ALT/AST (5.2%). The discontinuation rate for TEAEs was 14.8% for Rubraca-treated patients and 21.5% for the control arm.

Clovis Oncology will submit an expanded description of the TRITON3 results for presentation in a scientific session at the Prostate Cancer Foundation Annual Scientific Retreat later this month and plans to submit additional data to a medical meeting in early 2023.

Rubraca is not currently approved in the chemotherapy-naïve mCRPC setting.

Source: "TRITON3 Phase 3 Trial Of Rubraca® (Rucaparib) Achieves Primary Endpoint In Men With Metastatic Castration-Resistant Prostate Cancer With BRCA Or ATM Mutations". 2022. Ir.Clovisoncology.Com.
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