Preliminary results from the TRITON2 study of rucaparib in patients (pts) with DNA damage repair (DDR)-deficient metastatic castration-resistant prostate cancer (mCRPC): Updated analyses

Abstract

Abstract Background Rucaparib has shown antitumour activity in pts with mCRPC and a deleterious DDR gene alteration. We present here updated analyses. Methods TRITON2 (NCT02952534) is an ongoing phase 2 study evaluating rucaparib 600mg BID in pts with mCRPC and a deleterious germline or somatic alteration in BRCA1, BRCA2, ATM, CDK12, or other prespecified DDR gene. Eligible pts have progressed on 1–2 lines of androgen receptor–directed therapy and 1line of taxane-based chemotherapy for mCRPC. Results As of 15 Feb 2019 (visit cutoff), 136 pts had received rucaparib and had ≥16 weeks of follow-up: 62 with a BRCA2 and 7 with a BRCA1 alteration (BRCA pts), 41 with an ATM alteration (ATM pts), 14 with a CDK12 alteration (CDK12 pts), and 12 with another DDR gene alteration (other DDR pts). Median duration of follow-up was 11.4mo (range 4.0–24.0). PSA and objective response rates (ORR) were 53.6% and 47.5% in BRCA pts (Table). ORR in BRCA pts with somatic alterations was 56.5% (95% CI, 34.5–76.8; 13/23) and 40.0% (95% CI, 16.3–67.7; 6/15) in pts with germline alterations. Some ATM and CDK12 pts had a reduction in target lesion diameter (≥30% decrease in 3ATM pts) or PSA level (≥50% decrease in 3ATM pts and 2 CDK12 pts); however, no objective responses were observed in ATM or CDK12 pts, and only 1ATM pt and 1 CDK12pt had a confirmed PSA response. Median (95% CI) time to PSA progression was 6.5 (5.7–7.5) mo, 3.1 (2.8–4.6) mo, and 3.5 (2.8–4.6) mo in BRCA, ATM, and CDK12 pts. The most common grade ≥3 treatment-emergent adverse event was anaemia/decreased haemoglobin (16.2%). Conclusions Consistent with prior reports, rucaparib demonstrates promising efficacy in pts with mCRPC and a germline or somatic BRCA or other DDR gene alteration. No objective responses have been observed in pts with an ATM or CDK12 alteration. The safety profile of rucaparib is consistent with prior reports in ovarian and prostate cancer. Updated data will be presented.Table846PDTableBy DDR gene with alterationBRCAATMCDK12Other DDR geneaBaseline disease characteristics, n/N (%)Gleason score ≥848/69 (69.6)17/41 (41.5)13/14 (92.9)8/12 (66.7)Measurable disease at baseline (per investigator)40/69 (58.0)15/41 (36.6)9/14 (64.3)12/12 (100)Efficacy outcomes, n/N (%) [95% CI]Confirmed investigator-assessed objective responseb19/40 (47.5)0/15 (0)0/9 (0)4/12 (33.3)c[31.5–63.9][0–21.8][0–33.6][9.9–65.1]Complete response2/40 (5.0)001/12 (8.3)Partial response17/40 (42.5)003/12 (25.0)Confirmed PSA responsed37/69 (53.6)1/41 (2.4)1/14 (7.1)5/12 (41.7)e[41.2–65.7][0.1–12.9][0.2–33.9][15.2–72.3]aIncludes 2 pts each with an alteration in FANCA, NBN, or PALB2 and 1 each with an alteration in BRIP1, BRIP1/CHEK2, CDK12/CHEK2, CHEK2, RAD51, or RAD51B.bDefined as confirmed complete or partial response per modified RECIST/PCWG3. Includes pts who had measurable disease at baseline per the investigator and ≥16 weeks of follow-up.cResponders include 1pt each with a BRIP1, FANCA, PALB2, or RAD51B alteration.dDefined as≥50% reduction in PSA from baseline. Includes pts who had ≥16 weeks of follow-up.eResponders include 2 pts with a PALB2 alteration and 1pt each with a BRIP1, FANCA, or RAD51B alteration. CI, confidence interval; PSA, prostate-specific antigen. Clinical trial identification NCT02952534. Editorial acknowledgement Nathan Yardley, PhD, and Shannon Davis of Ashfield Healthcare Communications (Middletown, CT, USA), funded by Clovis Oncology, Inc. (Boulder, CO, USA). Legal entity responsible for the study Clovis Oncology, Inc. Funding Clovis Oncology, Inc. Disclosure W. Abida: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Clovis Oncology, Inc.; Advisory / Consultancy: Janssen; Advisory / Consultancy: MORE Health; Advisory / Consultancy: ORIC Pharmaceuticals; Research grant / Funding (institution), Travel / Accommodation / Expenses: GlaxoSmithKline; Honoraria (self): Caret Healthcare; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Zenith Epigenetics. A. Patnaik: Advisory / Consultancy: Janssen; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): GlaxoSmithKline. J. Shapiro: Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy, Travel / Accommodation / Expenses: Merck; Advisory / Consultancy: Astellas Pharma, Inc.; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Roche. N.J. Vogelzang: Advisory / Consultancy: Astellas Pharma, Inc.; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bayer; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Caris; Advisory / Consultancy: Janssen; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Sanofi Aventis. J. Zhang: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Sanofi; Research grant / Funding (institution): Astellas Pharma, Inc.; Research grant / Funding (institution): Bayer. A.D. Simmons: Shareholder / Stockholder / Stock options, Employee: Clovis Oncology, Inc. D. Despain: Shareholder / Stockholder / Stock options, Employee: Clovis Oncology, Inc. M. Dowson: Shareholder / Stockholder / Stock options, Employee: Clovis Oncology, Inc. T. Golsorkhi: Shareholder / Stockholder / Stock options, Employee: Clovis Oncology, Inc. S. Chowdhury: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Clovis Oncology, Inc.; Advisory / Consultancy, Speaker Bureau / Expert testimony: Astellas Pharma, Inc.; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Janssen; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Sanofi. All other authors have declared no conflicts of interest.