Wassim Abida, MD, PhD
Preliminary data from the ongoing phase II TRITON2 trial demonstrated a 44% confirmed objective response rate (ORR) by investigator assessment among evaluable men with BRCA1/2
-mutated metastatic castration-resistant prostate cancer (mCRPC) who were treated with the PARP inhibitor rucaparib (Rubraca).1
The findings were presented in a poster discussion at the 2018 ESMO Congress.
Among the men with BRCA1/2
alterations, 51% had a confirmed prostate-specific antigen (PSA) response to rucaparib, reported Wassim Abida, MD, PhD, and colleagues.
Based on initial trial data from TRITON2, rucaparib monotherapy received a breakthrough therapy designation from the FDA earlier this month as treatment for adult patients with BRCA1/2
-mutated mCRPC who have received at least 1 prior androgen receptor (AR)–directed therapy and taxane-based chemotherapy.
Treatment options are limited for men with mCRPC after androgen deprivation and taxane therapy. In the disease, up to 25% of patients have a deleterious germline and/or somatic mutation in BRCA1, BRCA2, ATM
, or other homologous recombination repair (HRR) gene alterations.
TRITON2 is an international, multicenter, open-label study evaluating men with mCRPC associated with 1 of 13 HRR gene alterations. The presentation at ESMO by Abida, medical oncologist, Memorial Sloan Kettering Cancer Center, New York City, and principal investigator, included data from 85 patients enrolled through June 29, 2018, at which time the median duration of follow-up was 5.7 months (range, 2.6-16.4).
Patients enrolled had disease progression on AR-directed therapy and 1 prior taxane-based chemotherapy. They had to have an ECOG performance status of 0 or 1 and could not have received prior PARP inhibitor, mitoxantrone, cyclophosphamide, or platinum-based chemotherapy. They were treated with rucaparib, 600 mg twice daily, until radiographic progression or discontinuation for another reason. Tumors were assessed radiographically every 8 weeks for 24 weeks, then every 12 weeks. PSA assessments were performed every 4 weeks.
The primary endpoints include confirmed ORR per RECIST/Prostate Cancer Clinical Trials Working Group 3 criteria in patients with measurable disease at baseline and PSA response in patients with no measurable disease at baseline.
The evaluable population for PSA response included 45 patients with BRCA1/2
mutations. The population evaluable for radiographic response included 25 patients with BRCA1/2
The median age of the evaluable 45 patients with BRCA1/2
mutations was 71 years (range, 50-88); most (62.2%) had an ECOG performance status of 1. In this group, prior therapies included abiraterone (Zytiga; 55.6%), enzalutamide (Xtandi; 73.3%), both abiraterone and enzalutamide (31.1%), docetaxel (Taxotere; 95.6%), cabazitaxel (Jevtana; 8.9%), sipuleucel-T (Provenge; 13.3%), and radium (11.1%). Forty patients (88.9%) had bone metastases, 62.2% had nodal metastases, and 42.2% had visceral metastases. Fifteen patients (33.3%) had a germline BRCA1/2
mutation and 30 (66.7%) had a somatic BRCA1/2
The median treatment duration in patients with a BRCA1/2
alteration was 4.4 months. Among patients with BRCA
mutations, 21 (80.8%) remain on study.
All 11 investigator-assessed radiographic responses (ORR, 44.0%; 95% CI, 24.4%-65.1%) in the patients with BRCA
-mutated tumors were partial responses. Nine other patients (36.0%) had stable disease. The median duration of response in these patients has not yet been reached.
There were no radiographic responses in the 5 patients with ATM
mutations or the 8 with CDK12
mutations. Four 4 of the 5 patients (80%) with ATM
mutations and 5 of the 8 (62.2%) with CDK12
mutations had stable disease as their best response. Two of 8 patients (25%) with other HRR gene alterations had a radiographic response; both were partial responses.
Of the 23 patients with BRCA1/2
mutations who had PSA responses, 17 occurred in those with measurable disease at baseline and 6 in patients with no measurable disease. Zero of 18 patients with ATM
mutations and 1 of 13 (7.7%) with CDK12
mutations had a PSA response. Two of 9 (22%) with other HRR gene alterations had a PSA response.
Enrollment of patients with CDK12
alterations has been halted per protocol based on the lack of responses observed.
The preliminary safety data for rucaparib in men with mCRPC have been consistent with those observed in patients with ovarian cancer and other solid tumors. The most common treatment-emergent adverse events (TEAEs) of any grade in all 85 patients included asthenia/fatigue in 38 (44.7%), nausea in 36 (42.4%), anemia/decreased hemoglobin in 24 (28.2%), and decreased appetite in 24 (28.2%). Anemia was the most common grade ≥3 adverse event (15.3%). Five patients (5.9%) discontinued therapy due to a nonprogression-related TEAE. One patient died due to disease progression.