Ryan Scott

Cytotoxic and cystostatic antitumor activity was observed in patients with metastatic castration-resistant prostate cancer (mCRPC) who progressed on androgen receptor (AR)-targeting therapy who underwent treatment with sabizabulin (VERU-111), recently presented data indicate.

The utilization of sabizabulin in patients yielded significant and durable objective tumor responses, according to results of a phase 1b/2 trial (NCT03752099) presented at the 2022 American Urological Association Annual Meeting.

Moreover, the median radiographic progression-free survival (rPFS) was 11.4 months (95% CI, 29.63-65.79).

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 

®. “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.

1. 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.

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The utilization of sabizabulin in patients yielded significant and durable objective tumor responses, according to results of a phase 1b/2 trial (NCT03752099) presented at the 2022 AUA Annual Meeting.

Sabizabulin active in metastatic castration-resistant prostate cancer

Translocation renal cell carcinoma (tRCC) is a rare and aggressive form of kidney cancer that has not historically received the same research attention as more common forms of RCC. Available treatment options consist mainly of therapies that have succeeded in other forms of RCC; however, these treatments are often unsuccessful in tRCC patients.

Now, Ziad Bakouny, MD, MSc , an internal medicine resident at Brigham and Women's Hospital, says ongoing research is focusing specifically on gaining an understanding of the biology and genomic drivers of tRCC.

“If we do not understand the biology [of the disease], we are not going to be able to target it correctly,” Bakouny said. “Currently, extrapolating treatments from clear cell RCC has not yielded optimal outcomes. Because of this, we want to understand the biology more to be able to target the disease better, treat patients better, and ultimately get them better clinical outcomes.”

, Bakouny, discussed ongoing research into the genomic drivers and biology of tRCC that could lead to improved outcomes for patients.

Could you provide some background on the treatment of tRCC?

: tRCC is a very rare disease that affects primarily young patients, and interestingly, females more than males. It is thought to account for 1% to 5% of all RCCs in adults, and in children, it accounts for 20% to 50% of kidney cancers. The disease is aggressive, and what we know about is actually that we do not know that much. There have been large studies on more frequent forms of kidney cancer, including clear cell RCC and papillary RCC, and because of these efforts, there is quite a bit understood about the genomic drivers of this disease.

However, rarer forms, like tRCC, have not been studied as extensively, and we do not know much about them. This contributes to the fact that we do not have many therapies that work for them. All the therapies currently used for tRCC are extrapolated from clear cell RCC, as well as from other forms of kidney cancer.

The reason it is important to understand the biology of tRCC is because it is aggressive, and patients, unfortunately, often have poor outcomes, Additionally, it disproportionately affects young patients, and there is a significant burden of disease for these young patients, particularly young women.

What were the key takeaways from this research? Did investigators identify any clinical molecular features of the disease?

Because of how rare this disease is, we realized that we could not do this on our own, in the sense that no one center anywhere across the world would have been able to get enough samples to study the molecular characteristics of the disease, in addition to the clinical characteristics. What we did was pull data from approximately 10 different data sets that were publicly available, including some of our own. We put it all together and we analyzed it, using some unorthodox methods, to be able to ask the questions about what the molecular characteristics of these tumors are, what is driving these tumors, and what therapies might work for them.

To do this, we pulled the data together and included genomic data such as DNA level analyses and mutations. We also looked at fusions because these tumors are known to be driven by a characteristic fusion involving the 

 family of genes. Then we looked at was transcriptomic data, as well, and wanted to know what the transcriptomic characteristics of these tumors are. Finally, we looked at clinical responses to therapies.

In the DNA-level analyses of data, we found that these tumors have a silent genome—they do not have a lot of mutations, they do not have a lot of copy number alterations. Despite that, they do seem to have some recurrent alterations that we have identified, primarily 9p21.3 deletion, which is the 

 locus that seems to be deleted in up to 20% of these tumors, as well as a few mutations that we detected in DNA damage response genes and 

 genes. That was the mutational bucket, in fusion bucket, it is known that these tumors evolve 

 genes. What we noticed is that the pattern of how these fusions form, what they conserve as part of these genes, differs between fusions. These genes seem to conserve the C-terminal domain, the DNA binding domain, of these proteins well, but depending on the actual gene itself, there are different parts of the protein domains that are conserved in the fusion product between them, so we that was characterized.

On the transcriptomic side of things, what we found is that these tumors seem to have a distinct transcriptional signature that is different from all other forms of RCC. This is characterized by genes that are known to be targets of 

. We then used cell lines to transfect the fusion into this alliance [and were then able to] deduct that the transcriptional program of these tumors appears to be induced by the fusion itself. We then asked, what is this transcriptional program and what is it characterized by? What we found is that it is characterized by activation of the NRF2 transcriptional program, and that is a program that has been known to be activated across several malignancies.

Now that we know what the genomic characteristics are, we know what the fusion looks like, and we know what the transcriptomics look like for these tumors, we are left with the clinical response. What we found is that, as expected, these NRF2-expressing tumors do not seem to respond well to targeted therapies, which explains the usually poor outcomes seen in this patient population. We used to treat clear cell RCC with targeted therapies like mTOR inhibitors and VEGF inhibitors, and because of the NRF2 activation, we see poor responses to those with tRCC. However, they [do seem to] respond well to immune checkpoint inhibitors. We used our own data, as well as data from tRCCs that were identified post hoc in the phase 3 IMmotion151 trial (NCT02420821) to show that these tumors respond well to immune checkpoint inhibitors. This is still preliminary data, but given how rare this disease is, we believe they are convincing data that patients with these tumors may do well on immune checkpoint inhibitors or immune checkpoint inhibitor-based combinations.

What are some next steps for this research?

I am excited that through our study, and from multiple other studies that have been done in this space, we now have a firmer grasp on what the genomics of these tumors are and what the drivers are. What remains to be understood is how these interplay with each other. For instance, what is the fusion doing with the 

 loss? How are they cooperating to drive the pathogenesis of these tumors?

The next step that I am excited about is figuring out the underlying biology and following up on some of the signals that we have seen on how [these factors] interact with each other to drive tumor pathogenesis. The hope is that with a more granular understanding of these tumors, we will be able to develop specific therapies that target the pathogenic processes and be able to improve the outcomes of these patients, which is still a huge unmet clinical need.

Are there any recent therapeutic developments in tRCC, that should be highlighted that you want to discuss?

Unfortunately, the main therapeutic developments are the ones I previously mentioned as part of our study and others. These therapeutic developments are using the treatments we already have for RCC and seeing how they do in tRCC. This alludes to some of our own work that was just mentioned about how immune checkpoint inhibitors might do well in these tumors. There is corroborating data from other studies that have shown similar things, and right now, that is the most exciting space, in terms something that is clinically actionable. That said, the next steps are targeting the underlying biology of disease. That is what may drive improvement in the outcomes of patients with these tumors.

Ziad Bakouny, MD, MSc, highlights efforts to gain an understanding of the biology and genomic drivers of the rare and aggressive form of kidney cancer. 

Ryan Scott

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Sabizabulin active in metastatic castration-resistant prostate cancer

Dr. Bakouny details ongoing research in translocation renal cell carcinoma