Rucaparib Bests Physician's Choice for BRCA+ mCRPC

The PARP inhibitor rucaparib (Rubraca) improved median radiographic progression-free survival (rPFS) by 4.8 months compared with physician’s choice of therapy for men with BRCA-altered metastatic castration-resistant prostate cancer (mCRPC), according to findings from the phase 3 TRITON3 study (NCT02975934) presented at the 2023 Genitourinary Cancers Symposium and simultaneously published in the New England Journal of Medicine.^1,2

In the open-label phase 3 trial, the median rPFS was 11.2 months (95% CI, 9.2-13.8) with rucaparib compared with 6.4 months (95% CI, 5.4-8.3) with physician’s choice of therapy in those with BRCA-mutant mCRPC (HR, 0.50; 95% CI, 0.36-0.69; P <.001). In the intention-to-treat (ITT) population, which also included those with ATM alterations, the median rPFS was 10.2 months (95% CI, 8.3-11.2) with rucaparib compared with 6.4 months (95% CI, 5.6-8.2) with physician's choice (HR, 0.61; 95% CI, 0.47-0.80; P <.001).

“Rucaparib reduced risk of imaging-based progression or death by half in patients with BRCA alterations, and it improved vs both docetaxel and second-generation ARPI [androgen receptor pathway inhibitor] therapy in the BRCA subgroup and ITT populations,” said lead investigator Alan H. Bryce, MD, Consultant, Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic in Phoenix, Arizona, in a presentation of the data.

In the study, patients were randomized 2:1 to either rucaparib at 600 mg twice daily (n = 270) or physician’s choice of docetaxel (n = 75) or second-generation ARPI (n = 60), which included abiraterone acetate (Zytiga; n = 28) and enzalutamide (Xtandi; n = 32). Prior to study enrollment, most patients (approximately 80%) had received 1 or more prior therapies for CRPC. The most common gene alterations in the rucaparib arm were BRCA1 (n = 29), BRCA2 (n = 172), and ATM (n = 69), which was a stratification factor and similar in the control arm. Cross over was allowed upon progression, with 75% of patients in the control arm crossing over to receive rucaparib.

Baseline characteristics were similar between arms, with a median age of 70 years in the rucaparib arm compared with 71 years in the control arm. ECOG performance status was split evenly between a score of 0 and 1 and most patients were either M0 (39% to 41%) or M1 (41% to 48%). The median PSA in the investigational arm was 26.9 ng/mL compared with 28.8 ng/mL in the control group. The most common site of metastases was the bone (84% to 87%), with nearly half patients having bone-only metastases (39% to 43%). Nearly two-thirds of patients had a Gleason score of 8 or more.

In those with ATM mutations but not BRCA alterations, there was no added benefit for rucaparib compared with physician’s choice of therapy. In this group, the median rPFS was 8.1 months (95% CI, 5.5-8.3) with rucaparib compared with 6.8 months (95% CI, 4.0-10.4) for physician’s choice (HR, 0.95; 95% CI, 0.59-1.52).

In patients with BRCA-mutated mCRPC, differences were observed depending on the control agent administered. For patients receiving docetaxel, the median rPFS was 8.3 months (95% CI, 6.1-9.9), representing a 47% reduction in the risk of progression or death with rucaparib (HR, 0.53; 95% CI, 0.37-0.77). The median rPFS was shorter with the second-generation ARPI, at 4.5 months (95% CI, 3.3-5.8), which was a 62% improvement in rPFS favoring the PARP inhibitor (HR, 0.38; 95% CI, 0.25-0.58). “These results extended through to the ITT population,” Bryce said.

The interim overall survival (OS) findings were not yet statistically significant, as the data continue to mature. At the time of the analysis, data maturity was 53.6% compared with a target of 70%, noted Bryce. In the BRCA-mutant mCRPC arm, median OS was 24.3 months (95% CI, 19.9-25.7) with rucaparib compared with 20.8 months (95% CI, 16.3-23.1) with physician’s choice (HR, 0.81; 95% CI, 0.58-1.12; P = .21). In the ITT group, the median OS was 23.6 months (95% CI, 19.7-25.0) and 20.9 months (95% CI, 17.5-24.4) for rucaparib and the control arms, respectively (HR, 0.94; 95% CI, 0.72-1.23).

Looking at each control treatment specifically, the median OS with docetaxel was 18.9 months (95% CI, 15.0-23.1) and the median OS with second-generation ARPI was 22.1 months (95% CI, 15.9-28.3). The hazard ratios for these groups were 0.75 (95% CI, 0.51-1.11) and 0.81 (95% CI, 0.52-1.27), respectively.

Adverse effects (AE) led to treatment discontinuation for 15% of patients in the rucaparib arm compared with 22% of those in the physician's choice group. There were 5 deaths related to an AE in the rucaparib arm (2%) compared with 3 in the control group (2%). None of these events were deemed to be related to the study treatment. The most common grade 3 or greater AEs in the rucaparib arm were anemia or decreased hemoglobin (24%), fatigue (7%), neutropenia (7%), thrombocytopenia or decreased platelet count (6%), and increased liver enzymes (5%).

“The primary toxicity that was more prominent in the rucaparib group was anemia, with 29% of rucaparib-arm patients receiving at least 1 blood transfusion vs 2% for those receiving physician's choice of therapy,” Bryce said. “The rest of the toxicities are in line with all previously published studies.”

The TRITON3 study was funded by Clovis Oncology, Inc, which announced plans in October 2022 to submit data from the study to the FDA as a supplemental new drug application for the BRCA subgroup of patients. However, in December 2022, Clovis announced it had voluntarily initiated Chapter 11 proceedings to declare bankruptcy, and is seeking to sell its assets, leaving the future for rucaparib and the TRITON3 data in question. The agent was initially granted an accelerated approval for BRCA-mutated mCRPC in May 2020.³

References

1. Bryce AH, Piulats JM, Reaume MN, et al. Rucaparib for metastatic castration-resistant prostate cancer (mCRPC): TRITON3 interim overall survival and efficacy of rucaparib vs docetaxel or second-generation androgen pathway inhibitor therapy. J Clin Oncol. 2023;41(suppl 6):18. doi:10.1200/JCO.2023.41.6_suppl.18
2. Fizazi K, Piulats JM, Reaume MN, et al. Rucaparib or physician’s choice in metastatic prostate cancer. N Engl J Med. Published online February 16, 2023. doi:10.1056/NEJMoa221467
3. FDA grants accelerated approval to rucaparib for BRCA-mutated metastatic castration-resistant prostate cancer. FDA. May 15, 2022. Accessed February 17, 2023. https://www.fda.gov