Ulka N. Vaishampayan, MBBS, Examines Oral Formulation of Docetaxel With Ritonavir, ModraDoc006/r, in Metastatic CRPC

Ulka N. Vaishampayan, MBBS
Professor of Internal Medicine
Director, Phase I Program
University of Michigan Rogel Cancer Center
Ann Arbor, MI

Results from a randomized phase 2 trial (NCT04028388) of oral docetaxel plus ritonavir (ModraDoc006/r) in patients with metastatic castration-resistant prostate cancer (mCRPC) were recently presented in a poster at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting and indicated significant safety benefits vs standard treatment with intravenous (IV) docetaxel.

Ulka N. Vaishampayan, MBBS, professor of internal medicine and director of the Phase I program at the University of Michigan Rogel Cancer Center in Ann Arbor, and lead investigator of this study, spoke with CancerNetwork^® about the efficacy of the novel oral formulation of docetaxel, ModraDoc006/r, particularly its safety profile vs IV docetaxel.

Results showed ModraDoc006/r to be equally effective in treating mCRPC vs IV docetaxel with a safety profile that was comparable and even improved across certain standard adverse effects (AEs) associated with the drug’s administration. ModraDoc006/r at bi-daily once weekly dosages of ModraDoc006 at 20/20 mg and ritonavir at 200/100 mg showed radiological progression-free survival (PFS) results that were similar to IV docetaxel. The oral treatment minimized gastrointestinal and hematologic AEs, alopecia, and neuropathy vs the standard IV treatment. Investigators concluded that these results warranted further development of ModraDoc006/r.

CancerNetwork^®: What was the rationale for assessing the addition of ritonavir to oral docetaxel in metastatic CRPC?

Vaishampayan: The addition of ritonavir to the oral form of docetaxel [ModraDoc006/r] helps with the metabolism of the taxane and allows for continued drug exposure without the peaks induced by the infusion of docetaxel. The oral dose is also more convenient [allowing us to] sustain twice-weekly doses and levels of docetaxel without significant toxicity from those peak doses while maintaining continued efficacy. That was the preclinical testing that was done with ModraDoc006/r.

What among these findings stood out to you?

This study is a phase 2 randomized trial comparing ModraDoc006/r with IV docetaxel. [Patients in the control group were given] IV docetaxel at the standard dose of 75 mg/m² every 21 days. Patients with mCRPC who had not received prior chemotherapy [were eligible to] enroll. Patients could have been treated with prior androgen receptor pathway inhibitors and progressed [on that treatment]. Initially, we only required measurable disease to assess response rates by RECIST1.1. However, the study was later expanded to allow bone-only metastases as well as measurable disease, if necessary. Because of that, we changed response monitoring criteria to [radiographic] PFS per PCWG3 [Prostate Cancer Working Group 3] criteria. The striking thing about this study is that the toxicity profile of ModraDoc006/r was remarkably better [vs IV docetaxel]. There were no severe cytopenias, no neutropenia, no significant thrombocytopenia, and no evidence of febrile neutropenia. The chances of hair loss were smaller and neuropathy, which is another significant toxicity of IV docetaxel, was not noted to the same degree [with ModraDoc006/r]. Moreover, the efficacy was well maintained. After the first few patients were enrolled, we changed the starting dose of ModraDoc006/r to 20/20 mg instead of 30/20 mg, which was established as the recommended phase 2 dose in the phase 1b trial. However, in an older, pretreated patient population such as those with mCRPC, we found the 20/20 mg dose to be well tolerated and it maintained efficacy similar to IV docetaxel.

Where do you foresee future research efforts going with this regimen?

The sample size of this study was about 50 patients per arm with a 1:1 randomization. In addition, after we reduced the dose and allowed bone-only metastases in Cohort 2 of the study, there were 31 patients on the lower starting dose of ModraDoc006/r that were treated. Even given the attenuated sample size, the results of this study are hypothesis-generating and justify moving further along into a phase 3 trial. The next phase of the development of ModraDoc006/r is planned within the pretreated mCRPC setting, and a larger study will be planned.

What do you hope your colleagues took away from this presentation?

The biggest thing that comes out of this presentation is that an oral chemotherapy such as ModraDoc006/r was better tolerated and convenient. We hope that this will make chemotherapy much more applicable to the majority of patients with mCRPC. There is a big obstacle of IV treatment for patients with comorbidities, especially those at risk of cytopenia and neuropathy who are not candidates for chemotherapy. We hope ModraDoc006/r will allow the majority of patients with mCRPC to benefit [from docetaxel].

Reference

Vaishampayan UM, Keessen M, Shore ND, et al. A phase 2 randomized study of oral docetaxel plus ritonavir (ModraDoc006/r) in patients with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2022;40(suppl 16):5016. doi:10.1200/JCO.2022.40.6_suppl.5016