High Efficacy of the PARP Inhibitor Olaparib Combined with High-Dose Chemotherapy and Autologous Stem-Cell Transplant for Refractory Lymphomas

More active HDC are needed for ASCT for refractory/poor-risk relapsed lymphomas. Enhancement of the activity of HDC through combination 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, which initiates DDR. Olaparib, the first FDA-approved PARP inhibitor for use in selected solid tumors, has shown synergy with conventional-dose chemotherapy, albeit with increased myelotoxicity. We studied in vitro the interaction of olaparib, epigenetically potentiated with the histone deacetylase (HDAC) inhibitor vorinostat, with a combination of gemcitabine/busulfan/melphalan (GemBuMel), which we had developed previously. We observed a markedly increased cytotoxicity of vorinostat/GemBuMel when combined with olaparib in refractory B- and T-cell lymphoma lines (Valdez et al., Leuk Lymphoma 2017;58:2705-16). Our preclinical work led us to design and clinically study olaparib plus vorinostat/GemBuMel with ASCT in refractory lymphomas.

PATIENTS AND METHODS: Patients ages 15-65 with refractory lymphomas and adequate end-organ function were eligible for this phase I trial (NCT03259503). Olaparib was given from day -11 to -3, at 7 dose levels (DL1-DL7), ranging from 25 to 300 mg PO twice daily. Vorinostat was given at 1,000 mg PO daily (days -10 to -3). Gemcitabine was administered at 2,475 mg/m²/day IV (days -8 and -3), infused as a loading dose of 75 mg/m² followed by continuous infusion at 10 mg/m²/min over 4 hours. Busulfan dosing targeted 4,000 μM.min^-1/day IV (days -8 to -5). Melphalan was infused at 60 mg/m²/day IV (days -3 and -2). Patients with CD20⁺ tumors received rituximab (375 mg/m²) IV on day -10. ASCT was on day 0. The trial goals were to identify the recommended phase 2 dose (RP2D) of olaparib, and estimate the overall (ORR), and complete response (CR) rates, event-free (EFS) and overall survival (OS) rates of the regimen.

RESULTS: Between 10/19 and 06/22 we enrolled 30 patients: 18 Hodgkin, 6 DLBCL and 6 T-NHL, median age 34 (20-61), median prior lines of therapy 3 (range, 2-7), 8 prior CAR-T or other cellular immunotherapies. Eleven patients had PET+ tumors at HDC (3 of them in PD). An olaparib dose of 150 mg PO BID (DL4) was identified as the RP2D. There was 1 TRM (sepsis) at DL5. The toxicity profile was similar to that of vorinostat/GemBuMel without olaparib and included mucositis (17 grade 3, 11 grade 2), asymptomatic elevation of transaminases (10 grade 3, 7 grade 2), hyperbilirubinemia (7 grade 3, 2 grade 2, with no cases of VOD/SOS), colitis (2 grade 3, 3 grade 2), diarrhea (3 grade 3, 3 grade 2), and asymptomatic bradycardia during the HDC regimen (6 grade 1). Neutrophils and platelets engrafted promptly. The ORR and CR rates were both 100%. At median follow-up of 16 (range, 2-34) months, the EFS and OS rates are both 90%. There were only two relapses at 4 and 7 months, respectively, both in patients treated at DL1. Olaparib markedly inhibited PAR levels (measured by ELISA in PBMNC), which decreased significantly from baseline to day -5 (and became undetectable in those patients treated at the RP2D), with rapid PARylation recovery on day -2 (around 12 hours after the last dose of olaparib).

CONCLUSION: In this first trial combining a PARP inhibitor and an HDAC inhibitor with HDC, olaparib/vorinostat/GemBuMel was safe and highly active in refractory relapsed lymphomas, including post-CAR-T relapses. Olaparib, in combination with HDAC inhibition, strongly potentiates HDC through inhibition of PARylation and DDR during treatment. The clinical data are encouraging and this approach warrants further evaluation.

Nieto:Affimed: Other: Scientific advisory Board, Research Funding; Secura Bio: Research Funding; Astra Zeneca: Research Funding. Srour:Orca Bio: Research Funding. Alousi:Genetech: Consultancy; Mallinkrodt: Honoraria; Prolacta: Consultancy; Sanofi / Kadmon: Honoraria; Incyte: Honoraria, Research Funding. Popat:Novartis: Research Funding; Iovance: Consultancy; Incyte: Research Funding; Bayer: Research Funding; Abbvie: Research Funding. Gulbis:EUSA Pharma: Honoraria. Shigle:Takeda: Membership on an entity's Board of Directors or advisory committees. Strati:Roche Genentech: Consultancy; Sobi: Research Funding; ALX Oncology: Research Funding; Astrazeneca Acerta: Research Funding; Kite Gilead: Consultancy; TG Therapeutics: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Hutchinson MediPharma: Consultancy. Ahmed:Seagen: Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Tessa Therapeutics: Consultancy, Research Funding; Xencor: Research Funding; Chimagen: Consultancy, Research Funding; Myeloid Therapeutics: Consultancy. Steiner:Seagen: Research Funding; BMS: Research Funding; GSK: Research Funding; Rafael Pharmaceuticals: Research Funding. Westin:Abbvie/GenMab: Consultancy; Iksuda: Consultancy; Merck: Consultancy; Calithera: Consultancy, Research Funding; MonteRosa: Consultancy; ADC Therapeutics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding; MorphoSys/Incyte Corporation: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; SeaGen: Consultancy. Iyer:Salarius Pharmaceuticals, Inc.: Consultancy. Champlin:Kadmon: Consultancy; Omeros: Consultancy; Actinium: Consultancy; Johnson &Johnson: Consultancy; General Oncology: Other: Data Safety Monitoring Board; Bluebird: Other: Data Safety Monitoring Board; Cell Source Inc.: Research Funding. Shpall:Fibroblasts and FibroBiologics: Consultancy; adaptimmune: Consultancy; NY blood center: Consultancy; Navan: Consultancy; axio: Consultancy; Affimed: Other: License agreement; Takeda: Patents & Royalties; Bayer: Honoraria.

Olaparib is a PARP inhibitor approved for ovarian cancer, breast cancer and prostate cancer. We use it in this trial to inhibit DNA damage repair after high-dose chemotherapy for lymphomas.