Up to 30% of mCRPC men harbor DDR defects and may benefit from PARP inhibitors (PARPi) after abiraterone/enzalutamide and docetaxel failure. CBZ was recently shown to improve overall survival (OS) in this population, though benefit by DDR status is unknown. We assessed CBZ activity in men with mCRPC according to their DDR status.
In this retrospective multicenter study, mCRPC patients (pts) who received CBZ were included if their DDR profile from tissue was available. Gene panels included at least BRCA1/2, ATM, CDK12 CHEK1/2, FANCA/FANCL, PALB2, RAD51. DDR positive (DDR+) pts could have had any deleterious germline or somatic DDR. For each DDR+ pts, DDR negative (DDR-) pts were randomly selected after matching for the same molecular test and institution, in a 1:1 ratio. PSA decline, radiological progression-free survival (rPFS) and OS were assessed.
A total of 190 pts were included: 95 DDR+ and 95 DDR-. DDR+ pts were younger than DDR- (66 vs 69 years, p=0.026). The Gleason score was ≥8 in 66% and 55%, metastases (mts) were found at diagnosis in 51% and 41%, respectively. At CBZ start, pts had received a median of 2 prior life-prolonging agents, visceral mts in 24% and 26%, ECOG ≤1 in 78% and 80%, and a median PSA of 91 and 77 ng/ml, respectively. Among DDR+ pts, 40 (42%) had BRCA defects and 43 (45%) received a PARPi. A 50% PSA decline was achieved with CBZ in 29 (32%) and 33 (36%) in DDR+ and DDR- pts (p=0.64). Median rPFS was 5.33 months [95%CI 4.34-7.04] and 5.75 months [95%CI 4.67-7.27] (p=0.55), and median OS was 15.4 months [95%CI 12.16-26.6] and 11.5 months [95%CI 9.76-14.4] (p=0.036), respectively. An ECOG≥2 and visceral mts were independently associated with shorter OS. Outcomes of DDR+ pts are depicted in the Table, according to their sequence with PARPi. Table: 614MO
|CBZ no PARPi n=53||CBZ before PARPi n=24||CBZ after PARPi n=18|
|Median prior lines||2||2||3|
|ECOG ≤1||36/53 (72%)||22/24 (92%)||12/18 (67%)|
|Visceral mts||13/53 (25%)||5/24 (21%)||4/18 (22%)|
|50% PSA decline All pts BRCA+||16/51 (31%) 10/39 (26%)||10/24 (42%) 6/14 (43%)||3/18 (17%) 0/10 (0%)|
|Median rPFS (months) [95%CI]||6.15 [3.68-8.38]||5.97 [3.98-8.05]||3.09 [0.98-6.57]|
|Median OS (months) [95%CI]||12.9 [10.2-20]||42.5 [20.2-67.4]||7.2 [5.29-13.41]|
CBZ is active in both DDR+ and DDR- mCRPC men. Activity may be lower in pts pre-treated with a PARPi, pending validation.
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C. Llacer Perez: Travel/Accommodation/Expenses: Astellas Pharma, Angelini Pharma. G. Gravis Mescam: Honoraria (institution): Pfizer, BMS, MSD, AstraZeneca, Astellas, Janssen, Bayer; Advisory/Consultancy: BMS, Pfizer, AstraZeneca, Janssen, Sanofi, Ipsen, Bayer; Travel/Accommodation/Expenses: BMS, Pfizer, AstraZeneca, Janssen, Sanofi, Ipsen, MSD. A. Fléchon: Honoraria (self): AZ Sanofi, Astellas, Janssen AAA; Travel/Accommodation/Expenses: AZ Sanofi, Astellas, Janssen. P. Barthélémy: Honoraria (self): Astellas; Advisory/Consultancy: Janssen-Cilag, Sanofi, MSD, BMS, Pfizer, Novartis, Ipsen, Roche; Travel/Accommodation/Expenses: BMS, Amgen, Pfizer, Janssen-Cilag, Roche, Ipsen. C. Helissey: Advisory/Consultancy: Sanofi, Janssen, Astellas, Roche, AstraZeneca. C. Pobel: Travel/Accommodation/Expenses: Sanofi, Ipsen, Sandoz. E. Castro Marcos: Advisory/Consultancy: AstraZeneca, Bayer, Janssen; Speaker Bureau/Expert testimony: Astellas, AstraZeneca, Bayer, Janssen, Pfizer; Research grant/Funding (institution): AstraZeneca, Bayer, Janssen; Travel/Accommodation/Expenses: AstraZeneca, Bayer, Janssen, Roche. A. Thiery-Vuillemin: Honoraria (self): Pfizer, AstraZeneca, Sanofi, Janssen, Novartis, Ipsen, Roche/Genentech, Bristol-Myers Squibb, MSD, Astellas Pharma; Advisory/Consultancy: Pfizer, AstraZeneca, Sanofi, Janssen, Novartis, Ipsen, Roche, Bristol-Myers Squibb, MSD, Astellas Pharma; Research grant/Funding (institution): Pfizer; Travel/Accommodation/Expenses: Roche, MSD, Janssen, Bristol-Myers Squibb. G. Baciarello: Honoraria (self): Janssen, Roche; Advisory/Consultancy: Amgen, Astellas Oncology, Janssen, Roche; Travel/Accommodation/Expenses: Astellas Oncology, Ipsen, Janssen, Roche. E. Orillard: Honoraria (self): Astellas, Janssen; Travel/Accommodation/Expenses: Pfizer, Amgen. K. Fizazi: Honoraria (self): Astellas Pharma, Bayer, Janssen, Sanofi; Advisory/Consultancy: Amgen (Inst), Astellas Pharma, AstraZeneca (Inst), Bayer, Curevac (Inst), ESSA (Inst), Janssen Oncology, Orion Pharma GmbH, Sanofi; Travel/Accommodation/Expenses: Amgen, Janssen. All other authors have declared no conflicts of interest.