Sabizabulin Yields Encouraging rPFS, Tolerable Toxicity Profile in Previously Treated mCRPC

Mark C. Markowski, MD, PhD

The utilization of sabizabulin (VERU-111) in patients with metastatic castration-resistant prostate cancer (mCRPC) who progressed on androgen receptor (AR)-targeting therapy yielded significant and durable objective tumor responses, according to results of a phase 1b/2 trial (NCT03752099) presented at the 2022 AUA Annual Meeting.

Moreover, the median radiographic progression-free survival (rPFS) was 11.4 months (95% CI, 29.63-65.79), and data suggest that cytotoxic and cytostatic antitumor activity was observed.

Of 29 patients with measurable disease in the intent-to-treat population, the objective response rate (ORR) was 20.7%; 1 had a complete response and 5 had partial responses. Fourteen of 48 patients (29%) saw a form of prostate-specific antigen (PSA) decline, and 4 patients (8%) saw a greater than 50% in PSA decline.

“We saw objective response rates in the 20% to 30% range,” Mark C. Markowski, MD, PhD, an assistant professor of oncology at Johns Hopkins Medicine, said in an interview with OncLive^®. “However, the most impressive [finding] we saw was PFS, which extended beyond 9 months. In certain patients, they have been on the study for 2 to 4 years now with preferable disease control. We see preliminary tumor shrinkage, as well as durable disease control responses that are really benefiting patients.”

Because sabizabulin is an oral agent that targets the cytoskeleton while inhibiting microtubule polymerization, its use in the patient population was hypothesized to demonstrate favorable activity in prostate cancers that are resistant against taxane, vinblastine, doxorubicin, enzalutamide (Xtandi), and abiraterone acetate (Zytiga).

Sabizabulin has had broad success in other malignancies, such as triple-negative breast cancer, cervical cancer, lung cancer, ovarian cancer, and pancreatic cancer, all of which demonstrated activity in those who were resistant standard-of-care regimens.

In the phase 1 portion of the phase 1b/2 trial, investigators enrolled patients with mCRPC and had progressed on AR-targeting therapy, as well as up to 1 taxane. The phase 2 portion of the study enrolled patients with mCRPC who had also progressed on AR-targeting agent therapy but only prior to intravenous chemotherapy.

“The phase 1 portion of the dose-escalation design included men who had at least 1 prior novel AR-targeted therapy, and up to 1 taxane chemotherapy. We enrolled 39 patients, and allowed for intra patient dose escalation,” Markowski explained, adding that, “We worked our way up the cohort and identified a dose at 63 mg given daily continuously. [This] was the recommended phase 2 dose.”

The study was conducted at 7 sites, with Johns Hopkins Kimmel Comprehensive Cancer Center being the lead center. Thirty-nine patients were enrolled on the phase 1 portion of the study utilizing the 2-part dosing strategy of 3+3 dose escalation on days 1 to 7 every 21 days to determine the maximum-tolerated dose. Patients remained on treatment until disease progression or stopping due to treatment-related toxicity.

Once the 63-mg daily dose was determined, the phase 2 portion of the study was conducted in 13 medical centers in the United States with 41 patients enrolled. The phase 2 portion is an open-label study and aimed to evaluate both safety and efficacy of the oral therapy.

Regarding baseline characteristics, the median age was 74 years (range, 61-92) in the phase 1 portion and 73 years (range, 57-86) in the phase 2 portion. Twenty-one patients (54%) had an ECOG score of 0 in the phase 1 and 30 (73%) did in the phase 2 portion; 16 patients (41%) and 10 (24%) had an ECOG score of 1, respectively in the phase 2 portion. Two patients (5%) had an ECOG score of 2 in the phase 1 portion and 1 (2%) did in the phase 2 portion.

All patients had progressed on prior treatment, and metastatic disease locations ranged from bone only, lymph node only, bone and lymph node, visceral only, bone and visceral, as well as lymph node and visceral. More than half (55% in phase 1 and 59% in phase 2) had bone-only metastases.

Prior therapies in the phase 1 portion included abiraterone (36%), enzalutamide (20%), abiraterone and enzalutamide or apalutamide (Erleada) or proxalutamide (44%), or taxane (9%). In the phase 2 group, these treatments included abiraterone (17%), enzalutamide (32%), abiraterone and enzalutamide or apalutamide or proxalutamide (39%), apalutamide or proxalutamide (12%), or taxane (7%).

The utilization of the oral agent did not cause any significant neutropenia or neurotoxicity and the safety profile was found to be well tolerated and similar to that of AR-targeting agents. AEs were mostly of grades 1/2.

Of the 54 patients in the phase 1b expansion cohort and phase 2 study, grade 3 or higher AEs included diarrhea (7.4%), fatigue (5.6%), nausea (1.9%), increased alanine aminotransferase levels (5.6%), aspartate aminotransferase levels (3.7%), back pain (1.9%), and vomiting (1.9%).

“We did not see similar toxicities to taxane chemotherapy including cytopenias and we did not see neutropenia, which is a known toxicity of the taxane chemotherapy,” Markowski commented. “This is fairly common for an orally dosed drugs, which were low grade and [included] fatigue.”

Regarding next steps, the data of this phase 1b/2 trial has led to the start of the phase 3 VERACITY trial (NCT04844749). This trial is meant to evaluate the efficacy of sabizabulin in patients who have failed prior treatment with at least 1 AR-targeting agent.

“The VERACITY trial is a phase 3 study that's already accruing [and it] is a randomized trial in mCRPC. Post 1 novel AR-targeted therapy, patients are randomized to receive sabizabulin or an alternate AR-targeted therapy. The primary endpoint is rPFS,” Markowski concluded.

Reference

Markowski MC, Eisenberger MA, Pieczonka C, et al. Sabizabulin has both cytotoxic and cytostatic activity in Phase 1b/2 clinical of men with metastatic castration resistant prostate cancer who progressed on androgen receptor targeting agents. Presented at: 2022 American Urology Association Annual Meeting; May 13-16, 2022; New Orleans, LA. Abstract MP27-15.