Abstract 659P
Background
Rucaparib has shown clinical activity in mCRPC pts with a BRCA1 or BRCA2 (BRCA) alteration in TRITON2 (NCT02952534). Here, we report rucaparib pharmacokinetics (PK) in mCRPC pts and investigate exposure and safety/efficacy correlations.
Methods
Pts in TRITON2 received a starting dose of rucaparib 600 mg BID. The PK analysis population included pts who had ≥1 dose and ≥1 evaluable PK concentration. Sparse plasma PK data were analysed with a PPK model developed for ovarian cancer (OC). ER analyses were conducted with selected safety and efficacy endpoints. Covariate effects were also explored.
Results
The PK analysis population included 199 mCRPC pts. Rucaparib exposures were consistent with those observed in OC pts, suggesting no difference in rucaparib PK by tumour type or sex. Exposure-efficacy analyses in 113 mCRPC pts with a BRCA alteration suggested no statistically significant and plausible exposure-efficacy relationships between dose-corrected steady AUC and investigator-assessed objective response rate (ORR) or other measures. Covariate analysis suggested that pts with higher baseline prostate-specific antigen (PSA; as a continuous variable) had lower investigator-assessed ORR, and pts with measurable disease at baseline had a higher PSA response rate than pts with nonmeasurable disease. In the PK analysis population, the ratio of actual to nominal cumulative dose (based on 600 mg BID starting dose) was 0.9 during rucaparib treatment. Statistically significant correlations with dose-corrected steady-state Cmax were observed for grade ≥2 creatinine elevation. Covariate analysis suggested that pts with higher baseline haemoglobin (as a continuous variable) had a lower incidence of grade ≥3 haemoglobin decreases after rucaparib exposure.
Conclusions
Rucaparib PK in mCRPC pts was comparable to that in OC pts. Significant correlation was observed between exposure and grade ≥2 creatinine elevation. This is consistent with observations in other rucaparib studies and may be due to PARP inhibitor–mediated inhibition of renal transporters (ie, MATE1 and MATE2-K). These analyses support the use of rucaparib in mCRPC pts with a starting dose of 600 mg BID.
Clinical trial identification
NCT02952534.
Editorial acknowledgement
Editorial support funded by Clovis Oncology was provided by Frederique H. Evans, MBS, of Ashfield Healthcare Communications.
Legal entity responsible for the study
Clovis Oncology, Inc.
Funding
Clovis Oncology, Inc.
Disclosure
S. Chowdhury: Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Clovis Oncology; Advisory/Consultancy, Speaker Bureau/Expert testimony: Astellas; Advisory/Consultancy, Speaker Bureau/Expert testimony: Bayer; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: BeiGene; Advisory/Consultancy, Speaker Bureau/Expert testimony: Janssen; Advisory/Consultancy, Speaker Bureau/Expert testimony: Pfizer; Honoraria (self): GlaxoSmithKline; Shareholder/Stockholder/Stock options: Curve.life. A. Patnaik: Advisory/Consultancy: Exelixis; Advisory/Consultancy: Janssen; Advisory/Consultancy: Jounce Therapeutics; Honoraria (self), Research grant/Funding (self): Clovis Oncology ; Research grant/Funding (self): Prime Inc; Research grant/Funding (self): Roche; Research grant/Funding (self): Merck; Research grant/Funding (self): Progenics; Research grant/Funding (self): Bristol Myers Squibb; Research grant/Funding (self): GlaxoSmithKline. J. Shapiro: Advisory/Consultancy, Travel/Accommodation/Expenses: Amgen; Advisory/Consultancy: Astellas; Advisory/Consultancy: Ipsen; Advisory/Consultancy, Travel/Accommodation/Expenses: Merck; Advisory/Consultancy: Roche. A.H. Bryce: Honoraria (self): Astellas; Honoraria (self): Bayer. R. McDermott: Advisory/Consultancy: Bayer; Advisory/Consultancy, Travel/Accommodation/Expenses: Janssen; Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Travel/Accommodation/Expenses: Celgene; Research grant/Funding (self): Clovis Oncology; Research grant/Funding (self): Amgen; Research grant/Funding (self): Bayer; Research grant/Funding (self): Merck; Research grant/Funding (self): Bristol Myers Squibb. B. Sautois: Advisory/Consultancy: Clovis Oncology; Advisory/Consultancy: Astellas; Advisory/Consultancy, Travel/Accommodation/Expenses: Janssen; Advisory/Consultancy: Sanofi. N.J. Vogelzang: Advisory/Consultancy: Clovis Oncology; Advisory/Consultancy: Astellas; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Bayer; Advisory/Consultancy, Shareholder/Stockholder/Stock options: Caris; Advisory/Consultancy: Eisai; Advisory/Consultancy: Janssen; Advisory/Consultancy: Merck; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Sanofi; Full/Part-time employment, Editor: UpToDate. R. Bambury: Advisory/Consultancy: Bayer; Advisory/Consultancy: Janssen; Advisory/Consultancy: Roche; Advisory/Consultancy: Pfizer; Travel/Accommodation/Expenses: Abbvie; Travel/Accommodation/Expenses: Ipsen; Travel/Accommodation/Expenses: Pfizer; Leadership role, Co-Founder: Portable Medical Technology. J. Zhang: Advisory/Consultancy: Clovis Oncology; Advisory/Consultancy, Research grant/Funding (self): AstraZeneca; Advisory/Consultancy: Bayer; Advisory/Consultancy: Dendreon; Advisory/Consultancy: Merck; Advisory/Consultancy: Sanofi; Advisory/Consultancy: Seattle Genetics; Research grant/Funding (self): Astellas Pharma; Research grant/Funding (self): Bayer. M. Green: Full/Part-time employment: Certara ; Advisory/Consultancy: Clovis Oncology. J. Beltman: Shareholder/Stockholder/Stock options, Full/Part-time employment: Clovis Oncology. D. Despain: Shareholder/Stockholder/Stock options, Full/Part-time employment: Clovis Oncology. A.D. Simmons: Shareholder/Stockholder/Stock options, Full/Part-time employment: Clovis Oncology. S.P. Watkins: Shareholder/Stockholder/Stock options, Full/Part-time employment: Clovis Oncology. A. Golsorkhi: Shareholder/Stockholder/Stock options, Full/Part-time employment: Clovis Oncology. J. Xiao: Shareholder/Stockholder/Stock options, Full/Part-time employment: Clovis Oncology. W. Abida: Advisory/Consultancy, Research grant/Funding (self), Travel/Accommodation/Expenses: Clovis Oncology; Advisory/Consultancy: Janssen Pharmaceuticals; Advisory/Consultancy: MORE Health; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy, Travel/Accommodation/Expenses: ORIC Pharmaceuticals; Research grant/Funding (self): AstraZeneca ; Research grant/Funding (self): Zenith Epigenetics. All other authors have declared no conflicts of interest.