Rucaparib Shows Meaningful Antitumor Activity in BRCA1/2-Mutated mCRPC

Rucaparib (Rubraca) demonstrated encouraging antitumor activity with a manageable safety profile in patients with BRCA-mutant metastatic castration-resistant prostate cancer, according to updated results from the phase 2 TRITON2 trial (NCT02962534) published in the Journal of Clinical Oncology.¹

In a total of 115 patients with a BRCA alteration with or without measurable disease the confirmed objective response rates (ORR) was 43.5% (95% CI, 31.0%-56.7%; n = 27/62) per independent radiology review (IRR) and 50.8% (95% CI, 38.1%-63.4%; n = 33/65) per investigator assessment.

In the overall efficacy population, the prostate-specific antigen (PSA) response rate was 54.8% (95% CI, 45.2%-64.1%). The median radiographic progression-free survival (rPFS) was 9.0 months (95% CI, 8.3 months-13.5 months) and 8.5 months (95% CI, 8.1 months-11.2 months) according to the IRR and investigator assessment. Overall survival (OS) data were not mature at the time of the analysis, however the Kaplan-Meier estimated 12-month OS was 73.0% (95% CI, 62.9%-80.7%).

“PARP inhibitors have been a welcome additional treatment option available for eligible mCRPC patients, and I’m pleased that this publication provides additional detail about the potential clinical benefit of [rucaparib] for patients,” Wassim Abida, MD, of Memorial Sloan Kettering Cancer Center, stated in a press release. “These additional data presented in this publication provide physicians important information to inform treatment decisions for their eligible patients.”_²

In the ongoing, international, open-label TRITON2 study, investigators enrolled patients who were diagnosed with mCRPC and progressed following 1 to 2 lines of next-generation androgen receptor (AR)-directed therapy and 1 taxane-based chemotherapy. Several deleterious BRCA alterations were represented on the trial, including BRCA1 (n = 13), BRCA2 (n = 102), germline (n = 44), and somatic (n = 71). Patients received a starting dose of oral rucaparib at 600 mg twice daily. Those who experienced grade 3 or higher, or persistent grade 2 treatment-related adverse effects (TEAEs) were permitted to receive dose reductions in decrements of 100 mg.

Key efficacy end points of the study included ORR and locally-assessed PSA response rate. Additionally, secondary end points of the trial included duration of response (DOR), rate of confirmed locally-assessed PSA response, time to PSA progression, rPFS, OS, and safety.

At baseline, 57 patients had measurable disease, which was confirmed by both IRR and investigator assessment. Investigators noted a median follow-up of 17.1 months (range, 7.6-31.5 months), as well as a median duration of treatment of 8.1 months (range, 0.5-30.3 months) for the overall population. As of December 23, 2019, 25.2% (n = 29) of patients remained on treatment.

The majority of IRR- and investigator-assessed patients experienced a best response of stable disease or better of 88.7% and 89.2%, respectively. Moreover, 8 patients had a confirmed complete response in soft tissue disease per blinded IRR and/or investigator assessment. Among these patients, 1 had hepatic metastases, 1 had non-nodal pelvic mass, and 6 had nodal-only disease at baseline per IRR; 1 had a BRCA1 mutation and 7 had a BRCA2 mutation.

Among those who experienced a response in the IRR-evaluable population, 70.4% of patients demonstrated a response by the first tumor assessment in week 8. Among IRR responders, the median DOR was not reached (NR; 95% CI, 6.4 months-NR). However, in the investigator-assessed population, the median DOR was 6.4 months (95% CI, 5.5-11.7 months). Approximately 15 of the 27 patients in the IRR population with a confirmed objective response had a DOR of 6 months or longer. In the IRR and investigator-evaluable populations, 64.5% and 63.1% of patients showed a 30% or greater reduction in target lesion size, respectively.

Moreover, in the overall population, 54.8% of patients had a confirmed PSA response (95% CI, 45.2%-64.1%), with the median time to PSA response of 1.9 months (95% CI, 1.3 months-1.9 months). The median time to PSA progression was 6.5 months (95% CI, 5.9-7.8 months). Additionally, 60% of patients showed a single best PSA reduction of 50% or greater from baseline.

ORRs proved to be similar for patients with BRCA-mutated mCRPC, although investigators identified a higher PSA response rate in patients with a BRCA2 mutation. Patients with a BRCA1 or monoallelic alteration experienced lower PSA responses of 15.4% and 11.1%, respectively, compared with the overall population. However, those with biallelic alterations and/or homozygous loss experienced a PSA response of 75.0% and 81.0%, respectively.

Regarding safety, the median treatment duration was 6.5 months (range, 0.5 months-26.7 months) with a median follow-up of 13.7 months (range, 4.2-28.2 months). TEAEs of any grade occurred in 99.1% of patients (n = 114), with grade 3 or higher TEAEs being reported in 60.9% of patients (n = 70).

Investigators found that 63.5% of patients had either a treatment interruption or dose reduction due to TEAEs. Treatment interruption because of a TEAE occurred in 56.5% of patients. The most common grade 3 or higher TEAE reported with the agent was anemia, at 25.2%. TEAE-related treatment interruption occurred in 56.5% of patients (n = 65) with the most common reasons being anemia (21.7%), thrombocytopenia (13.9%), and fatigue (9.6%). Dose reduction because of a TEAE occurred in 40.9% of patients on the study; the most common reasons for this were anemia (13.0%), fatigue (9.6%), and thrombocytopenia (7.0%).

Additionally, 7.8% of patients discontinued treatment because of a TEAE. Among those who discontinued treatment, 1 patient each withdrew because of acute respiratory distress syndrome, ALT/AST increased, anemia, balance disorder, cardiac failure, decreased appetite, fatigue and weight decreased, leukopenia and neutropenia, pneumonia, and prolonged QT. Three deaths due to TEAEs were reported, 2 of which were from pneumonia and prolonged QT; both incidences were considered unrelated to rucaparib.

“The phase 3 TRITON3 study…is ongoing to define the clinical benefit…of rucaparib in an earlier disease setting among patients with mCRPC associated with a BRCA or ATM alteration who have progressed after one next-generation AR-directed therapy and who have not received taxane-based chemotherapy in the mCRPC setting,” concluded the authors of the study. “Rucaparib is being compared with physician’s choice of next-generation AR-directed therapy or docetaxel and will provide additional evidence of the effects of rucaparib treatment in men with mCRPC.”

In May 2020, the FDA granted an accelerated approval to rucaparib for the treatment of adult patients with BRCA mutation–associated mCRPC who have been treated with AR-directed therapy and a taxane-based chemotherapy.

References

1. Abida W, Patnaik A, Campbell D, et al. Rucaparib in men with metastatic castration-resistant prostate cancer harboring a BRCA1 or BRCA2 gene alteration. J Clin Oncol. Published online August 14, 2020. doi:10.1200/JCO.20.01035
2. Journal of Clinical Oncology publishes additional data from Clovis Oncology’s TRITON2 clinical trial evaluating Rubraca (Rucaparib) for the treatment of mCRPC in patients with BRCA1/2 gene mutations. News release. Clovis Oncology. August 17, 2020. Accessed August 28, 2020. https://bit.ly/34fkOML