Rucaparib Responses Reached in Nearly Half of Men With BRCA+ mCRPC

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 mutations.

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 mutation.

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.

Invited discussant Joaquin Mateo, MD, PhD, from the Prostate Cancer Translational Research Group at the Vall d’Hebron Institute of Oncology in Barcelona, Spain, said that several studies agree that the prevalence of BRCA1/2 defects in mCRPC is 10% to 12%. “That’s a lot of patients that may benefit from a different therapeutic approach,” he said.

Caution is indicated when interpreting the TRITON2 results because the interim analysis was not preplanned “in a trial that is expected to recruit over 150 patients,” he indicated.

Nevertheless, the confirmed 44% ORR and the confirmed 51% PSA response rate in the BRCA1/2 population in TRITON2 compare favorably with those obtained with abiraterone (ORR, 14%; PSA response rate, 38%) in the COU301 trial² and with enzalutamide (ORR, 29%; PSA response rate, 54%) in the AFFIRM trial.³ “I think that’s very promising that if phase II trials confirm the data, we might have PARP inhibitors coming soon into the prostate cancer clinic for patients with mutations in BRCA1 and BRCA2,” said Mateo.

Rucaparib dose reductions due to TEAS were required in 29.4% of the 85 patients, he pointed out, “but on the other hand, it’s encouraging that only 5 patients needed to discontinue the drug, which means that those dose reductions were normally sufficient to manage toxicity,” he said.

References

1. Abida W, Bryce AH, Vogelzang NJ, et al. Preliminary results from TRITON2: a phase 2 study of rucaparib in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) associated with homologous recombination repair (HRR) gene alterations. Presented at: 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract PD793.
2. De Bone JS, Logothetis CJ, Molina A, et al; COU-AA-301 Investigators. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364(21):1995-2005.
3. Scher HI, Fizazi K, Saad F, et al; AFFIRM Investigators. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367(13):1187-97.

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