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

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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/m2 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.