Rucaparib Gets a Win in Metastatic Castration-Resistant Prostate Cancer

SAN FRANCISCO — Imaging-based progression-free survival (PFS) was significantly longer with the PARP inhibitor rucaparib (Rubraca) compared with physician’s choice of therapy in patients with BRCA or ATM-associated metastatic castration-resistant prostate cancer (CRPC), the phase III TRITON3 study showed.

All patients in the study had already progressed after treatment with a second-generation androgen receptor-pathway inhibitor (ARPI). And among those who had a BRCA alteration, the median imaging-based PFS was 11.2 months in patients who received rucaparib versus 6.4 months in those who received physician’s choice of therapy, which included either docetaxel or another second-generation ARPI (HR 0.50, 95% CI 0.36-0.69, P<0.001), reported Alan H. Bryce, MD, of the Mayo Clinic in Phoenix.

In the intention-to-treat population — which also included the patients with ATM alterations — the rucaparib group had a median imaging-based PFS of 10.2 months compared with 6.4 months in the control group (HR 0.61, 95% CI 0.47-0.80, P<0.001), according to findings presented at the Genitourinary Cancers Symposium and published simultaneously in the New England Journal of Medicine.

“Rucaparib reduced the risk of imaging-based progression or death by half in patients with BRCA alterations, and improved [imaging-based] PFS versus both docetaxel and second-generation ARPI therapy in the BRCA subgroup and the intention-to-treat population,” Bryce said during his presentation.

He and his colleagues also evaluated imaging-based PFS according to the therapy used in the control arm, which was shorter with docetaxel compared with rucaparib in the BRCA subgroup, at 8.3 months (HR 0.53, 95% CI 0.37-0.77, P=0.0009), and was shorter with the second-generation ARPIs abiraterone acetate (Zytiga) and enzalutamide (Xtandi), at 4.5 months (HR 0.38, 95% CI 0.25-0.58, P<0.0001).

In an exploratory analysis of the ATM subgroup, median imaging-based PFS was not significantly different between the rucaparib and control groups (8.1 vs 6.8 months; HR 0.95, 95% CI 0.59-1.52).

Overall survival (OS) results at 62 months were immature, but were not significantly different in the BRCA subgroup (24.3 months with rucaparib vs 20.8 months with physician’s choice, P=0.21), nor the intention-to-treat group.

In discussing the results from TRITON3, Elena Castro, MD, PhD, of the Instituto de Investigación Biomédica de Málaga in Spain, noted that the study helps answer several questions arising from the landmark PROfound study.

In that trial, a cohort of patients with a least one alteration in BRCA1, BRCA2, or ATM treated with the PARP inhibitor olaparib (Lynparza) had an imaging-based PFS that was significantly longer than that for patients treated with physician’s choice of enzalutamide or abiraterone.

She pointed out that most of the benefit in PROfound was driven by BRCA2 patients, noting that it was unclear if patients with ATM alterations benefitted from PARP inhibitors.

Castro also said that in demonstrating the benefit of rucaparib over that of docetaxel in both the BRCA and intention-to-treat groups, TRITON3 is the first study to provide data on how PARP inhibitors compare with taxanes in metastatic CRPC.

For this study, Bryce and colleagues randomized 405 patients 2:1 to receive 600 mg of oral rucaparib twice daily or docetaxel, abiraterone acetate, or enzalutamide. Patients had histologically or cytologically confirmed metastatic CRPC and a BRCA (302 patients) or ATM alteration (103), and had progressed after treatment with one previous second-generation ARPI, but no chemotherapy.

Median age in the rucaparib group was 70, and 74% were white, while median age in the control group was 71, and 76% were white. All patients had an Eastern Cooperative Oncology Group performance status score of 0-1.

Bryce and colleagues reported that the most common adverse events in the rucaparib group were fatigue, nausea, and anemia or decreased hemoglobin, and the most common grade ≥3 adverse events were anemia or decreased hemoglobin, neutropenia or a decreased neutrophil count, and fatigue. The most common adverse events in the control group were fatigue, diarrhea, and neuropathy, and the most common grade ≥3 adverse events were fatigue and neutropenia or a decreased neutrophil count.

Adverse events leading to treatment discontinuation were reported in 15% of patients in the rucaparib group and 22% in the control group. Death from an adverse event during treatment occurred in five patients in the rucaparib group and in three patients in the control group.

No cases of myelodysplastic syndrome or acute myeloid leukemia were reported.