Rucaparib delays disease progression in subgroup of chemotherapy-naïve mCRPC

The PARP inhibitor rucaparib (Rubraca) improved radiographic progression-free survival (rPFS) versus chemotherapy or second-line androgen deprivation therapy (ADT) in patients with metastatic castration-resistant prostate cancer (mCRPC) that harbored a deleterious BRCA or ATM mutation, according to topline findings from the phase 3 TRITON3 trial.1

Independent radiology review (IRR) determined that in the overall intent-to-treat (ITT) population of patients with a BRCA or ATM mutation, rucaparib led to a 3.8-month improvement in median rPFS versus the control arm of chemotherapy or second-line ADT, translating to a 39% reduction in the risk of disease progression or death. The rucaparib benefit was even more pronounced in the subgroup of patients with a BRCA mutation. In these patients, the median rPFS benefit for the PARP inhibitor vs the control arm was 4.8 months, translating to a 50% reduction in the risk of disease progression or death.

“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,” Alan H. Bryce, MD, chair of the Division of Hematology and Medical Oncology at the Mayo Clinic and principal investigator of the TRITON3 trial, stated in a press release. “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.”

The multicenter, open-label phase 3 TRITON3 trial enrolled 405 patients with chemotherapy-naïve mCRPC that harbored a deleterious BRCA or ATM mutation. The study accrued patients who had disease progression following prior treatment with an androgen receptor pathway inhibitor (ARPI), such as abiraterone acetate (Zytiga), enzalutamide (Xtandi), or apalutamide (Erleada).

After a protocol amendment, patients were allowed to have received a qualifying ARPI for either hormone-sensitive or castration-resistant disease; consequently, around 18% of enrolled patients had been treated with an ARPI for metastatic hormone-sensitive disease only.

Patients were randomized to rucaparib or the control arm comprised of physician’s choice of docetaxel, abiraterone acetate, or enzalutamide. Over half (55%) of patients in the control arm were treated with docetaxel. The primary end point of TRITON3 was rPFS per IRR in patients whose tumors harbored a deleterious BRCA1, BRCA2, or ATM mutation.

In the ITT population of 405 patients with BRCA or ATM mutations, the median rPFS was 10.2 months versus 6.4 months in the rucaparib arm (n = 270) vs the control arm (n = 135), respectively (HR, 0.61; 95% CI, 0.47-0.80; P = .0003).

Among the subgroup of patients with BRCA mutations treated with rucaparib (n = 201), the median rPFS was 11.2 months versus 6.4 months in the physician’s choice control arm (n = 101; HR, 0.50; 95% CI, 0.36-0.69; P <.0001).

The investigators also did an exploratory analysis of patients whose tumors harbored ATM mutations. In this subgroup, the median rPFS was 8.1 months for the rucaparib arm (n = 69) versus 6.8 months for the control arm (n = 34; HR, 0.97; 95% CI, 0.59-1.52; P = .8421)

While the overall survival (OS) data are not yet mature, the hazard ratio for OS favored rucaparib in the ITT population and BRCA subgroup. In the ATM subgroup, the hazard ratio for OS favored the control arm, although the confidence interval reflected no significant difference in outcomes between the 2 arms.

Regarding safety, there were no new safety signals in TRITON3 as compared with rucaparib’s label. Grade ≥3 treatment-emergent adverse events (TEAEs) that occurred in at least 5% of patients 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%). Overall, TEAEs led to treatment discontinuation in 14.8% vs 21.5% of the rucaparib vs control arms, respectively.

In the press release, Clovis Oncology, the developer of rucaparib, reported that it plans to submit expanded details from this interim analysis at the upcoming Prostate Cancer Foundation Annual Scientific Retreat and submit additional data for presentation at a medical conference early next year.

Rucaparib is currently approved by the FDA for the treatment of adult patients with a deleterious BRCA mutation (germline and/or somatic)-associated mCRPC who have been treated with androgen receptor-directed therapy and a taxane-based chemotherapy. The PARP inhibitor is not currently approved for use in the chemotherapy-naïve mCRPC setting.

“This trial demonstrates the potential for rucaparib to treat men with early-stage metastatic castration-resistant prostate cancer,”Karim Fizazi, MD, PhD, principal investigator of the TRITON3 trial, medical oncologist at Gustave Roussy, and a full professor in Oncology at the University of Paris-Saclay, stated in the press release. “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.”

Reference

1. TRITON3 Phase 3 Trial Of Rubraca® (Rucaparib) Achieves Primary Endpoint In Men With Metastatic Castration-Resistant Prostate Cancer With BRCA Or ATM Mutations. Published online October 3, 2022. Accessed October 4, 2022. https://bit.ly/3CxMU6O