Colleen Moretti

Phase 1b/2 data shared during the 2021 ESMO Congress showed promising clinical activity with the novel agent sabizabulin (VERU-111) in patients with metastatic castration-resistant prostate cancer (mCRPC).

Both phases of the study involved patients who were previously treated with at least 1 androgen receptor-targeted therapy. The aim of the study was to evaluate the safety, maximum-tolerated dose, and efficacy of sabizabulin.

Patients included in the study were advanced in their treatment, Mark C. Markowski, MD, PhD, medical oncologist from John Hopkins University in Baltimore, Maryland, highlighted during his presentation. Many patients had previously been treated with abiraterone acetate (Zytiga), enzalutamide (Xtandi), a combination of both, or apalutamide (Erleada) or proxalutamide.

The phase 1b portion used a 3+3 design in 39 patients (median age, 74 years). Initially, each dose was administered orally on days 1-7 on a regimen of every 21 days. If this regimen was well tolerated and considered safe, the frequency was increased to a daily dosing on days 1-14 every 21 days. And if that was tolerated, patients then advanced to dosing daily until disease progression or toxicity.

In the phase 1b portion of the study, 10 patients reached at least 4 cycles of continuous dosing. Of that 10, 6 had any PSA response, 2 had at least a 50% PSA response. Additionally, two patients had a partial response, with the remaining 8 achieving stable disease. The median radiographic progression-free survival (rPFS) was greater than 12 months (range, 6.0-28+ months). And as of August 2021, 2 of the 10 patients remained on the study.

“That’s the most mature data we have. (It’s) a bit difficult given our dose escalation strategy,” Markowski noted.

The open-label phase 2 portion of the study comprised 44 patients (median age, 73 years) and evaluated the recommended dose of 63 milligrams (mg) daily. “We found that (the) recommended phase 2 dose was 63 milligrams per day, so daily dosing was safe and feasible,” Markowski explained.

The most common adverse events among 54 patients included diarrhea, fatigue, ALT and AST increases, all of which were mostly grade 1 and 2. Markowski added that there were no reports of clinically relevant neutropenia or neurotoxicity, “which we’ve seen before with taxane chemotherapy.”

Objective response rate in the intention-to-treat population (n = 26) was 20.7%, with 5 partial responses and 1 complete response. And in evaluable patients who qualified for a future phase 3 trial (n = 26) it was 23.1%.

In patients that received at least 63 mg (n = 55) median rPFS is estimated to be at least 7.4 months.

Markowski detailed that a phase 3 trial, known as VERACITY (NCT04844749), is currently underway and is evaluating 32 mg of sabizabulin for the treatment of mCRPC against an alternative AR-targeting agent. Patients in this study had prior treatment with 1 AR-targeted therapy, and no chemotherapy. This trial has a primary endpoint of rPFS.

1. Markowski M, Eisenberger M, Tutrone R, et al. Sabizabulin, an oral cytoskeleton disruptor, to treat men with metastatic castration resistant prostate cancer who failed an androgen receptor targeting agent. Presented at 2021 ESMO Congress; September 16-21, 2021; virtual. 578MO.

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Sabizabulin was well tolerated and associated with significant and durable objective tumor responses in patients with metastatic castration resistant prostate cancer.

Sabizabulin emerges as novel option in mCRPC

Yoga could help improve quality of life, promote an antitumor immune response, and reduce inflammation in men with prostate cancer undergoing prostatectomy, according to phase 2 results presented at the 2021 AUA Annual Meeting.

Yoga has a direct effect on the vagus nerve, which can shape how a person thinks, remembers, and feels. And patients with prostate cancer have a 20% to 30% incidence and prevalence of depression and anxiety.

In previous studies, yoga has demonstrated an improved quality of life for patients with cancer, as well as lower inflammation. Additionally, newer, emerging data has demonstrated that mindfulness exercises, such as yoga, can cause the frontal and limbic parts of the brain to structurally change.

“However, if you look at hierarchy of evidence, most data on immune benefits of yoga is from small series and case reports, no such data exists for prostate cancer. Given these findings of improvement in quality of life with yoga, we started looking at [the] role of yoga in prostate cancer,” said Dharam Kaushik, MD, associate professor in the department of urology at the University of Texas Health, San Antonio, during the presentation of the data.

The primary outcomes of this clinical trial [NCT02620033] was self-reported outcomes of quality of life at baseline, and 6 weeks. Secondary outcomes included immune cell status and cytokine levels, also at baseline and 6 weeks.

“We wanted to evaluate the quality of life from multiple vantage points, therefore we utilized 4 different quality of life questionaries,” Kaushik mentioned. Self-reported outcomes were assessed by the Expanded Prostate Index Composite (EPIC), Functional Assessment of Cancer Therapy-Prostate (FACT-P), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and Five Facets of Mindfulness Questionnaire (FFMQ).

The study consisted of 30 men who were newly diagnosed with localized prostate cancer and scheduled for a radical prostatectomy. Patients were randomized to either yoga (n = 15) or standard of care (n = 15). And patients in the yoga group, performed the activity for 60 minutes twice a week for 6 weeks before their prostatectomy and 3 to 6 weeks after.

Yoga “meaningfully” improved EPIC-sexual scores, FACIT-F, FACT general and FACT-P. In substratification, there were improvements in sexual, physical, and social well-being in the yoga group.

Additionally, participants in the yoga group demonstrated increased numbers of CD4+ (

There was also an increase in the natural killer cells IFNNK (

 = .041), “indicating a robust immune response,” Kaushik added.

Yoga also had an enhanced effect on antitumor activity, decreasing the numbers of regulator T-cells and myeloid-derived suppressor cells: CD11b+CD33+ (

There was also a decrease in cytokine cells including, G-CSF (

 = .032), which had shown to activate production endothelial cell and cytokines. Additionally, there was a decrease in MCP-1 (

 = .044), which are associated with proception against dementia, and FLt-3L (

 = .053) which has been linked to reducing chronic inflation, Kaushik mentioned.

The benefits demonstrated in this study require further investigation, the authors concluded in the abstract.

1. Kaushik D, Shah P, Mukherjee N, et al. A phase 2 randomized clinical trial of yoga in men with prostate cancer. Presented at: 2021 American Urological Association Annual Meeting; September 10-13, 2021; virtual. Abstract LBA02-03

Patients with prostate cancer have a 20% to 30% incidence of depression and anxiety; however, practicing yoga could improve their quality of life. 

Yoga may improve quality of life, immune response in patients with prostate cancer

Few studies on trials involving genitourinary cancers include data on participants’ smoking status, according to findings from a systematic review presented during the 2021 American Urological Association Annual Meeting.

“This study highlights a deficiency in urologic oncology [randomized, controlled trials’] to assess smoking status and participants. Given smoking’s effects on treatments, survival, and quality of life, we believe this is an important area that deserves more attention,” said Calvin C. Zhao, MD, New York University School of Medicine, during a virtual presentation at the meeting.

The primary outcome of this review was whether a study collected and reported data on their participants’ smoking status. Secondary outcomes included details on how smoking status was reported, if trial arms were balanced, and if smoking status was included in the analysis.

Using PRISMA guidelines, investigators identified 622 articles and 354 later met criteria to be used in the review. Only 8.2% (n = 30) of studies reported on smoking. Of those, 27 studies reported smoking in the manuscript or supplement. And 96.3% of studies reported at baseline qualitatively, such as “never,” “former,” or “current”, instead of quantifying pack-years or intensity.

Only 3 studies reported final or subgroup analyses that included smoking. And of that, 2 reported significant differences in outcomes that were associated with smoking status.

No study reported a smoking measurement instrument, non-cigarette tobacco use, and changes in smoking status over time.

Studies had to be published between May 2010 and May 2020; were randomized phase 2 through 4 trials; reported in the top 10 medicine, urology, or oncology journals by 2018 Impact Factor; reported primary analysis on data; must be a therapeutic intervention; and patients had to have had prostate, urothelial, or kidney cancer.

Studies included were mostly trials in prostate cancer (n = 210), were published in the 

 (n = 81), included patients from multiple continents (n = 119), reported on systematic therapies (n = 166), had an endpoint of overall survival (n = 102), and included patients with metastatic disease (n = 172). 

Limitations of this study include the timeline allowing for the inclusion of older articles, a publication bias for more positive and later stage trials, and journal scope.

“However, we believe our search strategy adequately captured the most impactful and landmark trials in contemporary urologic oncology literature,” Zhao said. “Until we have a better understanding of the tobacco use patterns of our patients, we cannot fully characterize the effects of smoking on cancer outcomes.”

Future directions should be using validated and standardized instruments to measure smoking status such as the Cancer Patient Tobacco Use Questionnaire (C-TUQ). As well as, report smoking status through the entire study period, integrate the data into Electronic Medical Record and smoking cessation counseling. Zhao said integrating these practices will allow for a “more robust analysis” of interactions between tobacoo use and clinical trial outcomes

“Ultimately, we believe there is a great need for more rigorous attention to smoking in urologic cancer patients. The way forward, we believe, is for urologists to play a more active role in not just smoking assessment, but also smoking cessation,” Zhao concluded.

1. Matulewicz R, Zhao C, Myrie A, et al. A systematic review and scoping analysis of smoking cessation after a urologic cancer diagnosis. Presented at: 2021 American Urological Association Annual Meeting; September 10-13, 2021; virtual. Abstract LBA02-01

“This study highlights a deficiency in urologic oncology [randomized, controlled trials’] to assess smoking status and participants. Given smoking’s effects on treatments, survival, and quality of life, we believe this is an important area that deserves more attention,” said Calvin C. Zhao, MD

Smoking status is rarely reported in genitourinary cancer trials

Findings from an exploratory analysis of the pivotal phase 3 CheckMate 9ER trial showed that frontline treatment with nivolumab (Opdivo) plus cabozantinib (Cabometyx) enhanced health-related quality of life (HRQoL) compared with sunitinib (Sutent) in patients with advanced renal cell carcinoma (RCC).

The QoL data, which were presented during the 2021 ASCO Genitourinary Cancers Symposium, also showed that, in the cohort of patients receiving the combination of the PD-1 inhibitor and the multikinase inhibitor, there was a delay in deterioration and a significant decreased risk for confirmed deterioration in HRQoL scores, including disease-related kidney cancer symptoms.

“These results indicate that the superior clinical efficacy of (nivolumab plus cabozantinib) over (sunitinib) is accompanied by the additional benefit of better HRQoL,” the researchers wrote. “Moreover, the HRQoL outcomes also support the acceptable tolerability profile of the (nivolumab plus cabozantinib) combination for patients with advanced HRQoL.”

Based on findings from the CheckMate 9ER trial, the FDA approved nivolumab/cabozantinib in January 2021 for use in the first-line setting for patients with advanced RCC.

In CheckMate 9ER, after a median follow-up of 18.1 months, nivolumab plus cabozantinib demonstrated superior progression free survival (hazard ratio [HR], 0.51; 

 <.0001), compared with sunitinib, in patients with advanced RCC with a clear cell component.

In their presentation, the researchers investigated patient-reported HRQoL outcomes further, including overall between-group comparisons of treatment groups and time to confirmed deterioration outcomes.

“In addition to the clinical outcomes, analyses of HRQoL, including time to confirmed deterioration in patient-reported outcome (PRO) scores may provide important insights for clinicians to assess the benefit/risk profile of potential new treatment regimens,” the researchers wrote.

To be eligible for the phase 3 trial, patients had to have previously untreated, advanced or metastatic RCC; a clear cell component; and any International Metastatic RCC Database Consortium (IMDC) risk. Patients were then stratified by IMDC risk score, tumor PD-L1 expression, and geographic region.

In total, patients were randomized 1:1 to receive either nivolumab at 240 mg IV every 2 weeks plus oral cabozantinib 40 mg daily (n = 323) or oral sunitinib at 50 mg daily for 4 weeks on, 2 weeks off (n = 328), until disease progression or toxicity.

PRO instruments were administered before treatment, and included Functional Assessment of Cancer Therapy Kidney Symptom Index-19 (FKSI-19) and the 3-level version of the EQ-5D (EQ-5D-3L). PRO completion rates for both arms were at 93% or more at baseline, and completion rates remained at 80% or more through week 91.

Longitudinal score changes from baseline in FKSI-19 total score and FKSI-19 disease-related symptom (DRS) scores favored nivolumab plus cabozantinib, compared to sunitinib, with an overall mean change from baseline of 2.90 (-0.51 vs -3.40; 

Mean change in EQ-5D-3L utility index and visual analog scale (VAS) scores also favored nivolumab plus cabozantinib, showing significant change through treatment with an overall change of 0.05 (-0.02 vs -0.07; 

 = .0011), respectively, with the combination versus sunitinib.

There was also a significant decreased risk of confirmed deterioration with nivolumab plus cabozantinib in FKSI-19 total score (HR, 0.64; 95% CI, 0.50-0.81; 

 = .0003) and FKSI-19 DRS score (HR, 0.62; 95% CI, 0.46-0.82; 

1. Cella D, Choueiri t, Blum S, et al. Patient-Reported Outcomes of Patients with Advanced Renal Cell Carcinoma Treated with First-Line Nivolumab Plus Cabozantinib Versus Sunitinib: the CheckMate 9ER Trial. Presented at: 2021 ASCO Genitourinary Cancer Symposium; February 11-13, 2021; Virtual. Abstract 285.

Based on findings from the phase 3 CheckMate 9ER trial, the FDA approved nivolumab/cabozantinib for use in the first-line setting for patients with advanced RCC.

Colleen Moretti

Articles

Sabizabulin emerges as novel option in mCRPC

Yoga may improve quality of life, immune response in patients with prostate cancer

Smoking status is rarely reported in genitourinary cancer trials

QoL boosted with nivolumab/cabozantinib in pivotal phase 3 RCC trial