ModraDoc006 Plus Ritonavir Shows Favorable Safety, Comparable Efficacy to IV Docetaxel in mCRPC

The combination of ModraDoc006—a novel, oral tablet formulation of docetaxel—and ritonavir produced comparable response rates and radiographic progression-free survival (rPFS) to that achieved with intravenous (IV) docetaxel in patients with metastatic castration-resistant prostate cancer (mCRPC), according to data from cohort 2 of a phase 2b trial (NCT04028388).¹

Data presented during the 2022 ASCO Annual Meeting showed that patients treated with ModraDoc006 plus ritonavir (n = 18) experienced an objective response rate (ORR) of 38.9% (95% CI, 17.3%-64.3%) vs 28.6% (95% CI, 8.4%-58.1%) with IV docetaxel (n = 14; P = .712). The prostate-specific antigen (PSA) response rate (PSA-RR) in the investigative and control arms were 48.3% (95% CI, 29.4%-67.5%) and 50.0% (95% CI, 30.6%-69.4%), respectively (P = 1.000).

The median rPFS that was not estimable (NE; 95% CI, 6.3-NE) in those who received ModraDoc006 plus ritonavir vs NE (95% CI, 7.9-NE) in those treated with docetaxel (n = 14). Additionally, in the investigative and control arms, the 6-month rPFS rates were 75% (95% CI, 52%-88%) and 88% (95% CI, 66%-96%), respectively; the 12-month rPFS rates were 61% (95% CI, 35%-79%) and NE, respectively (HR, 1.89; 95% CI, 0.62-5.80; P = .2567).

“The study results make a compelling rationale for evaluating this convenient, oral, effective, and well-tolerated therapy in an expanded pivotal program,” lead study author Ulka Nitin Vaishampayan, MBBS, the director of the Phase I Program at Rogel Cancer Center, Michigan Medicine, and a professor of internal medicine at the University of Michigan, and colleagues, wrote in a poster presentation.

ModraDoc006 is co-administered with ritonavir to enhance bioavailability. The oral administration of the regimen has potential advantages for patients, including convenience and the elimination of infusion-related reactions which removes the need for prophylactic steroids; the regimen may also come with safety benefits over the usual dose-limiting toxicities of taxanes. Preclinical research has found that the co-administration of docetaxel and ritonavir was active in several docetaxel- and cabazitaxel-resistant prostate cancer cell lines.

The open-label, randomized, phase 2 trial enrolled patients with progressive mCRPC who were treatment-naïve or previously treated with abiraterone acetate (Zytiga) or enzalutamide (Xtandi). Patients were also required to have measurable tumor lesions of at least 1.5 cm in the short axis or visceral lesions of at least 1 cm in the longest region, per RECIST v1.1 criteria.² Other key inclusion criteria included adequate hematological, renal, and hepatic functions; a World Health Organization performance status of 0 to 2; and a life expectancy of at least 12 weeks.

Specifically, cohort 2 of the trial comprised patients with mCRPC who had evaluable disease per RECIST v1.1 criteria and Prostate Cancer Working Group 3 (PCWG3) to enable the recruitment of a broader patient base.

If patients had with symptomatic brain metastases, received any prior treatment with a taxane or any treatment with investigational drugs, chemotherapy, or immunotherapy within 4 weeks of study treatment, they were excluded. Notably, patients were permitted to receive palliative radiotherapy before and during the trial, although not in the week prior to the start of treatment.

The study was designed to evaluate 100 total patients, with 50 patients in each 2-arm cohort. The recommended phase 2 dose of ModraDoc006 at 30 mg in the morning and 20 mg at night on days 1, 8, and 15 of every 21-day cycle was used in cohort 1.

In cohort 2, patients were randomized 1:1 to receive 20 mg of ModraDoc006 in the morning and 20 mg at night, plus 200 mg of ritonavir in the morning and 100 mg at night, on days 1, 8, and 15 of every 21-day cycle, or 75 mg/m² of IV docetaxel on day 1 of every 21-day cycle.

The primary end point of the trial was rPFS per PCWG3 criteria. Secondary end points included ORR, disease control rate, duration of response, PSA response, 6-month rPFS and PFS, time to progression, PSA-PFS; and time to first skeletal event. Safety and health-related quality of life were also evaluated.

A total of 31 and 33 patients were randomized into the ModraDoc006/ritonavir and docetaxel arms, respectively. Twenty-nine and 28 patients were evaluable in the full-set analysis, respectively, and 31 patients from each arm were evaluable for safety.

Among all enrolled patients in cohort 2, the median age was 69.5 years (range, 53-76) and 66.0 years (range, 50- 80) in the docetaxel and ModraDoc006/ritonavir groups, respectively. Moreover, 65.5% of patients on the ModraDoc006/ritonavir arm had measurable disease at baseline compared with 53.6% of those on docetaxel arm. Additionally, 82.8% of patients in the ModraDoc006/ritonavir group had any visceral disease at baseline vs 92.9% of those in the docetaxel group. In the investigative and control arms, 34.5% and 46.4% of patients, respectively, had bone-only disease at baseline.

The median time since diagnosis was 41.63 months (range, 3.1-161.3) and 38.67 months (range, 1.7-175.9) in the ModraDoc006/ritonavir and docetaxel arms, respectively. The median PSA at baseline was 2.09 ng/mL (range, 1.8-25) and 2.03 ng/mL (range, 1.6-2.6), respectively. Notably, 14.3% of patients in both arms received prior enzalutamide; 10.7% of patients in the ModraDoc006/ritonavir arm received prior abiraterone acetate vs 25.0% in the docetaxel group.

Regarding safety, no patients experienced any-grade anemia, leukopenia, or neutropenia in the ModraDoc006/ritonavir group compared with 16.1%, 16.1%, and 25.8%, respectively, in the docetaxel group. Moreover, there were significantly lower rates of peripheral neuropathy, alopecia, and infusion-related injections in the ModraDoc006/ritonavir group vs the docetaxel group.

Most adverse effects (AEs) reported in the ModraDoc006/ritonavir arm were grade 1. The most common AEs of any grade reported in the investigative arm included diarrhea (32.3%), nausea (29%), alopecia (22.6%), and vomiting (19.4%).

“Results of this study indicate that further development of ModraDoc006/ritonavir in mCRPC is warranted,” the study authors concluded.

References

1. Vaishampayan UN, Keessen M, Shore ND, et al. Phase 2 randomized trial of ModraDoc006/r, oral docetaxel plus ritonavir, versus intravenous docetaxel in metastatic castration resistant prostate cancer (mCRPC). J Clin Oncol. 2022;40(suppl 16):117. doi:10.1200/JCO.2022.40.6_suppl.117
2. ModraDoc006/r vs docetaxel IV in metastatic prostate cancer. ClinicalTrials.gov. Updated February 8, 2022. Accessed July 12, 2022. https://clinicaltrials.gov/ct2/show/NCT04028388