ASCO 2022: A Phase 2 Randomized Study of Oral Docetaxel plus Ritonavir (ModraDoc006/r) in Patients with mCRPC

(UroToday.com) The 2022 ASCO annual meeting featured a session on prostate cancer, including a presentation by Dr. Ulka Vaishampayan discussing a phase 2 randomized study of oral docetaxel plus ritonavir (ModraDoc006/ritonavir) in patients with mCRPC. Intravenous docetaxel and oral prednisone is a standard of care regimen in patients with mCRPC. ModraDoc006 is an oral formulation of docetaxel and to enhance bioavailability of ModraDoc006 it is co-administered with ritonavir, an inhibitor of cytochrome P450 3A4 and P-glycoprotein. The ModraDoc006 and ritonavir combination is active in multiple docetaxel and cabazitaxel-resistant prostate cancer cell-lines. This combination has potential advantages in terms of patient convenience, elimination of infusion-related reactions, as well as other safety benefits regarding typical dose-limiting toxicities for taxanes. In this trial, the oral combination (ModraDoc006/ritonavir) was compared to IV docetaxel in a randomized phase 2b study of patients with mCRPC evaluating two doses of ModraDoc006/ritonavir (30-20/200-100 mg and 20-20/200-100 mg). At ASCO 2022, data on outcomes in the larger cohort, receiving the lower dose, were presented.


Eligible patients had mCRPC, performance status of 0-1, and no prior chemotherapy for mCRPC. Sixty-two patients were enrolled in open label 1:1 randomized study comparing ModraDoc006/ritonavir 20-20 mg combined with 200-100 mg ritonavir in a bi-daily weekly schedule (“20-20/200-100 mg”), with IV docetaxel 75 mg/m2 in 21-day cycles. All patients received 5 mg oral prednisone twice daily. The trial schema is as follows:

ModraDoc006-0.jpg

The primary endpoint was radiographic progression free survival (rPFS) per PCWG-3 criteria. Secondary objectives included ORR, PSA-PFS, time to skeletal related events, disease control rate, duration of response, and safety assessments. Serum PSA and radiological evaluations were assessed at baseline, after cycle 3, 6, 10, 14, and 18, etc.

There were 31 patients enrolled on IV docetaxel 75 mg/m2 and 31 on ModraDoc006/ritonavir 20-20/200-100 mg. Of these, 57 were included in the analysis for rPFS, and 32 patients with measurable disease were included in the ORR analysis. The median PSA was 46 (range 1 to 1460 ng/ml), and prior therapy was with enzalutamide in 8 patients and abiraterone in 10 patients. ModraDoc006/ritonavir was better tolerated with 0% all grades neutropenia and anemia, as compared to 26% (19% ≥G3) and 16% respectively on IV docetaxel. Neuropathy was significantly reduced at 9.7% grade 1 only on ModraDoc006/ritonavir vs 9.7% grade 1 and 19.4% grade 2 on IV docetaxel, whereas alopecia was reduced to 16.1% grade 1 and 6.5% grade 2 on ModraDoc006/ritonavir vs. 22.6% grade 1 and 19.4% grade 2 on IV docetaxel. GI toxicities were broadly comparable with diarrhea 32% (3% ≥ grade 3) vs 29%, nausea 29% vs 13% and stomatitis 3% (grade 3) vs 13% (3% ≥ grade 3), respectively. A full summary of the safety results is as follows:

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The overall response rate for ModraDoc006/ritonavir was 38.9% (95% CI 17.3, 64.3) compared to 28.6% (95% CI 8.4, 58.1; p = 0.712) for IV docetaxel, and the PSA response rate was 48.3% (95% CI 29.4, 67.5) for ModraDoc006/ritonavir compared to 50.0% (95% CI 30.6, 69.4; p = 1.0) for IV docetaxel. Maximum tumor size reduction was comparable between the two arms: 

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The median time to rPFS was not reached in both arms of the trial.

Dr. Vaishampayan concluded this presentation discussing a phase 2 randomized study of oral docetaxel plus ritonavir (ModraDoc006/ritonavir) in patients with mCRPC with the following take-home messages:

  • ModraDoc006/ritonavir is an attractive therapeutic option for development in mCRPC
  • ModraDoc006/ritonavir at 20-20/200-100 mg demonstrated a favorable safety profile, with mild (mostly grade 1) GI-toxicities, no hematological adverse events, decreased neuropathy, and alopecia
  • Tumor and PSA response rates, as well as rPFS were comparable to IV docetaxel
  • The study results make a compelling rationale for evaluating this convenient, oral, effective, and well tolerated therapy in an expanded pivotal program
  • Results of this study indicate that further development of ModraDoc006/ritonavir in mCRPC is warranted

Presented by: Ulka N. Vaishampayan, MD, University of Michigan, Ann Arbor, MI 

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, June 3 – Mon, June 7, 2022. 

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