Phase 2 randomized trial of ModraDoc006/r, oral docetaxel plus ritonavir, versus intravenous docetaxel in metastatic castration resistant prostate cancer (mCRPC).
Authors: Ulka N. Vaishampayan, Marianne Keessen, Neal D. Shore, Elisabeth I. Heath, Robert Dreicer, Tomas Buchler, Péter Ferenc Árkosy, Tibor Csoszi, Pawel J. Wiechno, Evgeny Kopyltsov, Denis Kholtobin, Sergey Orlov, Aleander Nosov, Sergey Varlamov, Nicholas J. Vogelzang
Journal: Journal of Clinical Oncology (2022)

117 Background: Intravenous (IV) docetaxel and oral prednisone is a standard of care regimen in mCRPC. ModraDoc006 is a novel, oral tablet formulation of docetaxel. To enhance bioavailability, it is co-administered with ritonavir (/r), an inhibitor of cytochrome p450 3A4 and P-glycoprotein metabolic enzymes. The oral combination, denoted as ModraDoc006/r, may be superior to IV docetaxel in terms of safety profile, avoiding infusions, patient quality of life (QoL) and overall resource utilization. Safety of ModraDoc006/r in mCRPC was established in a previous phase Ib trial. Methods: We conducted an open label 1:1 randomized study of ModraDoc006/r bi-daily weekly dosing (BIDW) regimen versus IV docetaxel 75 mg/m 2 in 21-day cycles. Initially, BIDW 30-20 mg ModraDoc006 combined with 200-100 mg ritonavir was administered on days 1, 8 and 15 of a 21-day cycle. After 39 patients the starting dose was reduced to 20-20 mg BIDW with ritonavir 200 mg in the morning and 100 mg with the evening dose to improve tolerability. All patients received 5 mg oral prednisone twice daily. Primary endpoint was radiographic progression free survival (rPFS) per PCWG-3 criteria. Secondary objectives were ORR, PSA-PFS, time to skeletal related events, disease control rate, duration of response, and safety assessments. Patient reported outcomes and health-related QoL was assessed with treatment satisfaction and FACT-P questionnaires at baseline and after cycles 3, 6 and 10. Results: Enrollment is complete with 101 patients accrued; 49 on IV docetaxel, 52 on ModraDoc006/r (21 on 30-20 mg and 31 on ModraDoc006/r 20-20 mg). 69 patients had measurable disease and median PSA was 67ng/ml (range 0,2 to 1697 ng/ml). IV docetaxel vs ModraDoc006/r 30-20 mg and 20-20 mg demonstrated ORR of 39% vs 50% and 33%, and PSA responses of 57% vs 53% and 48%. All grades neutropenia and neuropathy was noted in 0% and 6% with ModraDoc006/r 20-20 mg therapy and was better than the incidence of 14% (5% ≥G3) and 14% with ModraDoc006/r 30-20 mg, and 27% (20% ≥G3) and 31% respectively on IV docetaxel. Alopecia was also reduced at 23% on ModraDoc006/r 20-20 mg and 29% on ModraDoc006/r 30-20 mg vs 43% on IV docetaxel. GI toxicities were slightly more frequent, but predominantly mild, in the ModraDoc006/r arm: at 20-20 mg dose, all grades diarrhea 32% (3% ≥G3), nausea 29% and stomatitis 3% (G3); at 30-20 mg dose 62% diarrhea (19% ≥G3), 38% nausea and 14% stomatitis (5% ≥G3); and in IV docetaxel, 24% diarrhea, 16% nausea and 10% stomatitis (4% ≥G3). Conclusions: Hematological toxicities and adverse events neuropathy and alopecia were lower with ModraDoc006/r than with IV docetaxel. ModraDoc006/r represents a convenient, oral, tolerable option for patients with mCRPC. ModraDoc006/r has comparable efficacy and a favorable tolerability profile as compared to IV docetaxel and merits further development in patients with mCRPC. Clinical trial information: NCT04028388.