At the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Dr. Johann de Bono and colleagues presented the dose-escalation part of the first-in-human trial of TAS3681 in patients with mCRPC.
For this trial, mCRPC patients with progressing disease after abiraterone and/or enzalutamide, and ≥1 additional chemotherapy, received TAS3681 in a 3+3 dose escalation design. QD or BID tablets were given in 28-day cycles and BID dosing at ≤600 mg was introduced to increase daily exposure while limiting Cmax. The primary endpoints for this trial included the incidence of dose-limiting toxicities and adverse events. Other endpoints included pharmacokinetics and antitumor activity per Prostate Cancer Clinical Trials Working Group 3 (PCWG3).
As of January 22, 2021, 56 pts in 10 cohorts were dosed (QD: 25, 50, 100, 200, 400, 600, 800, and 1000 mg; and BID: 300 and 400 mg):
The median age was 66 (56–79) years and patients had a median of 6 prior lines of systemic therapy. Of 41 patients evaluable for dose-limiting toxicities, 3 had confirmed dose-limiting toxicities: 1/10 evaluable patients at 600 mg QD (QT prolongation >480 ms) and 2/3 evaluable patients at 400 mg BID (1 patient with QT prolongation >480 ms, 1 patient with grade 3 hypertension). The most common treatment-related adverse events were: nausea (32 patients, 57.1%), hyperbilirubinemia (21 patients, 37.5%), fatigue (18 patients, 32.1%), vomiting (17 patients, 30.4%) and diarrhea (16 patients, 28.6%). Adverse events of QT prolongation were seen in 11 patients (19.6%), and treatment-related adverse events ≥ in grade 3 were reported in 12 patients (21.4%). TAS3681 exposure increased dose-dependently up to 600 mg QD and then plateaued. Steady-state was reached by Day 8 and accumulation ratios of AUC were approximately 2 to 6 times. Confirmed PSA declines of >50% from baseline were seen in the 600 mg QD (2 patients) and 300 mg BID cohorts (1 patient):
Antitumor activity was observed, with a tumor response rate of 23.1% in the 600 mg QD cohort (3 confirmed partial responses in 13 dosed patients), 22.2% in the 300 mg BID cohort (1 confirmed partial response and 1 unconfirmed complete response in 9 dosed patients), and 14.3% in the 400 mg BID cohort (confirmed partial response in 1/7 dosed patients). Responses occurred after 2–4 cycles of treatment. The longest duration of response to date is 16.2 months, and the 5 patients with confirmed partial response had a duration of response > 6 months with the exception of 1 patient who had a short follow-up period:
300 mg BID was found to be the best-tolerated dose with antitumor activity based on: (i) median treatment duration was longer in 300 mg BID than in 600 mg QD, (ii) daily exposure AUC was comparable between 300 mg BID and 600 mg QD; Cmax was lower in the BID cohort, (iii) both cohorts showed similar efficacy in terms of PSA response and tumor response, and (iv) 300 mg BID showed a slightly better safety profile than 600 mg QD.
Dr. de Bono concluded his presentation with the following take-home messages:
- TAS3681 is an oral androgen receptor full-length and androgen receptor-splice variant antagonist, which has a manageable safety profile and has antitumor activity against heavily pretreated, multi-drug resistant mCRPC at the recommended phase 2 dose of 300 mg BID
- The study expansion phase is enrolling patients who have progressed on abiraterone or enzalutamide +/- taxane chemotherapy
Clinical trial information: NCT02566772
Presented By: Johann de Bono, MD, MSc, Ph.D., FRCP, FMedSci, Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton, Surrey, United Kingdom
Written By: Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Virtual Annual Meeting #ASCO21, June, 4-8, 2021