The Combination of the PARP Inhibitor Olaparib with High-Dose Chemotherapy (HDC) and Autologous Stem-Cell Transplant (ASCT) Demonstrates High Activity for Refractory Lymphomas, Including Prior Failures of CAR-T

More effective HDC regimens are needed for refractory lymphomas. Enhancement of HDC activity with DNA damage repair (DDR) inhibitors is a promising but unexplored avenue. The enzyme poly(ADP-ribose) polymerase (PARP) catalyzes PARylation at the DNA damage site, initiating DDR. Olaparib, the first PARP inhibitor approved for selected solid tumors, is synergistic with standard-dose chemotherapy, albeit with more myelotoxicity. We previously observed a markedly increased cytotoxicity of vorinostat/gemcitabine (Gem)/busulfan (Bu)/melphalan (Mel) when combined with olaparib in lymphoma cell lines, which led us to clinically study this combination in refractory lymphomas.PATIENTS AND METHODS: Patients (pts) ages 15-65 with refractory lymphomas and adequate end-organ function were eligible for this phase I trial (NCT03259503), including olaparib dose escalation and dose expansion phases. Olaparib was given from day (d) -11 to -3, at 7 dose levels (DL1-DL7) at 25 to 300 mg PO BID. Vorinostat was given at 1,000 mg PO daily (d-10 to -3). Gem was infused at 2,475 mg/m2/day IV (d-8 and -3) as a loading dose of 75 mg/m2 followed by continuous infusion at 10 mg/m2/min over 4 hours. Bu dosing targeted 4,000 μM.min−1/day IV (d-8 to -5). Mel was infused at 60 mg/m2/day IV (d-3 and -2). Pts with CD20+ tumors received rituximab (375 mg/m2) IV (d-10). ASCT was on d0. The goals were to identify the recommended phase 2 dose (RP2D) of olaparib in this combination and estimate the ORR, CR, EFS and OS rates.RESULTS: Between 10/19-06/23 we enrolled 50 pts (23 Hodgkin, 18 aggressive B-NHL and 9 T-NHL); median age 35 (20-61); median 3 prior therapy lines (range, 2-7); prior failure of CAR-T in 17 pts; 23 patients had PET+ tumors at HDC (9 in PD). An olaparib dose of 150 mg PO BID (DL4) was identified as the RP2D. Neutrophils and platelets engrafted promptly. The ORR was 100% with 90% CR. At median follow-up of 22 months (range, 4-48), the EFS and OS rates are 74% and 86%, respectively. Among the 17 pts with prior CAR-T failure, the EFS and OS rates are 76% and 88%, respectively. There were 2 TRM (sepsis). The main extramedullary toxicity was mucositis (22 grade 3, 23 grade 2). Other reversible extramedullary toxicities included asymptomatic rise of transaminases and bilirubin (no cases of VOD/SOS), colitis and diarrhea. Olaparib markedly inhibited PAR levels in PBMNC, which decreased significantly from baseline to d-5 (and became undetectable in the patients treated at the RP2D), with rapid PARylation recovery on d-2 (12 hours after the last olaparib dose).CONCLUSIONS: This first trial combining a PARP inhibitor and HDC (olaparib/vorinostat/GemBuMel) shows that this novel approach is safe and highly active in refractory lymphomas, including pts with prior CAR-T failures. Olaparib, in combination with HDAC inhibition, strongly potentiates HDC through inhibition of PARylation and DDR. This novel approach warrants further investigation.