(UroToday.com) In the Presidential Symposium 2 of the European Society for Medical Oncology (ESMO) Annual Congress focusing on prostate cancer, Dr. Mark Markowski presented data from a phase 1/2 trial of sabizabulin in men with metastatic castration resistant prostate cancer (mCRPC).
Sabizabulin is a novel oral agent that functions to target and disrupt the cytoskeleton. There are two distinct mechanisms: the first targets the cytoskeleton to crosslink and inhibit microtubule assembly (androgen-receptor independent) and the second of which disrupts transport of the androgen receptor (androgen-receptor directed). Notably, it is not a substrate for multi-drug resistant proteins.
In the phase Ib component, the authors performed a dose-escalation among men with mCRPC following at least one oral androgen receptor targeting agent (with or without one prior line of taxane chemotherapy). This component of the study sought to address the maximum tolerated dose. Following this, the authors performed a phase II study among men with mCRPC following at least one oral androgen receptor targeting agent, but not prior taxane chemotherapy, to assess safety and efficacy.
In phase Ib, the authors enrolled 39 patients and utilized a 3+3 design with escalating oral dosing of 4.5 mg to 81 mg for 7 days on /14 days off drug per 21-day cycle, then was expanded to continuous daily dosing. The recommended phase II dose was 63 mg PO daily. This phase II portion enrolled 41 patients.
In terms of the safety profile, sabizabulin was well tolerated with the most common adverse events (>10% frequency) in patients that received 63 mg dose (n=54) including diarrhea, fatigue, ALT, and AST increases which were mostly Grade 1 and 2. Dosing holidays and dose reductions were sufficient to manage the infrequent grade 3 toxicities.
In terms of efficacy, in the phase Ib portion of the study, assessing men who were treated with 63 mg (n=14), the median duration of the study was 10.8 months (2.3-24.7months). Among the 10 men who reached at least four cycles of therapy, PSA responses were seen with a decrease in 6 of 10 men, decreases of 30% or more in 4 of 10 men, and decreases of 50% or more in 2 of 10 men. In the men with measurable disease (n=10), the ORR was 20% (n=2, with a further two objective responses in men who did not reach four cycles of dosing). The remaining 8 men had stable disease.
The median radiographic progression-free survival was in excess of 12 months with 2 men remaining on therapy as of August 2021.
Including the phase II data, in the ITT population of patients with measurable disease at baseline (n=29), the ORR (5PR +1CR observed) was 20.7%. Among those who would qualify for a phase III trial, this was somewhat higher (23.1%). Finally, among patients that received ≥ 63 mg (excluding baseline super scans) (n=55), the median rPFS is estimated to be at least 7.4 months with 5 men on the study as of August 2021.
These data have formed the basis of a phase II trial (VERACITY) based on evidence from this phase Ib/II clinical trial that oral 63mg daily dosing of sabizabulin has a favorable safety profile and chronic dosing is feasible.
Presented by: Mark C. Markowski, MD, PhD, Johns Hopkins Medicine, Baltimore, United States of America