Jordyn Sava

Rezvilutamide/ADT significantly improved rPFS and OS vs bicalutamide/ADT in patients with high-volume, metastatic, hormone-sensitive prostate cancer, and a tolerable safety profile was seen.

Findings from the phase 3 CHART study showed that rezvilutamide (SHR3680) plus androgen deprivation therapy (ADT) significantly improved overall survival (OS) and radiographic progression-free survival (rPFS) compared with bicalutamide (Casodex) plus ADT in patients with high-volume, metastatic hormone-sensitive prostate cancer.

Rezvilutamide is a novel androgen-receptor inhibitor with low blood–brain barrier penetration. Previous studies of rezvilutamide have demonstrated potent antitumor activity against metastatic castration-resistant prostate cancer.

The open-label phase 3 CHART study (NCT03520478) enrolled patients at 72 hospitals across China, Poland, Czech Republic, and Bulgaria.

 Patients were eligible for enrollment if they were male, aged 18 years or older, had an ECOG performance status of 0 or 1, a diagnosis of high-volume metastatic, hormone-sensitive prostate cancer, and had adequate hepatic, renal, heart, and hematological function. Patients who received previous chemotherapy or other localized treatment for prostate cancer were not included.

Patients were randomly assigned in a 1:1 ratio and administered either ADT plus rezvilutamide 240 mg or bicalutamide 50 mg orally once daily. Randomization was performed via an interactive response technology system and patients were stratified according to ECOG performance status and presence of visceral metastasis. This excluded lymph nodes.

The primary end points of the study were rPFS and OS and investigators evaluated the secondary end points of time to prostate specific antigen progression, time to skeletal-related events, objective, and time to initiation of a new antineoplastic therapy response rate.

A total of 792 patients were screened between June 28, 2018, and August 6, 2020, with 654 patients randomly assigned to receive rezvilutamide plus ADT (n=326) or bicalutamide plus ADT (n=328).

At the data cutoff of May 16, 2021, results from the pre-planned interim analysis for rPFS showed that the median follow-up duration was 21.2 months (interquartile range [IQR], 16.6-25.8). The rPFS with rezvilutamide was significantly improved vs the rPFS with bicalutamide (median rPFS not reached [95% CI, not reached [NR]-NR] vs 25.1 months [95% CI, 15.7-NR]; HR 0.44; 95% CI, 0.33-0.58; 

The preplanned interim analysis for overall survival had a data cutoff of February 28, 2022. Here, the median follow-up duration was 29.3 months (IQR 21.0-33.3), and treatment with rezvilutamide significantly improved OS vs treatment with bicalutamide (HR 0.58; 95% CI, 0.44-0.77; 

 = .0001). Additionally, the median OS with rezvilutamide was not reached (95% CI, NR-NR) vs not reached (36.2-NR) with bicalutamide.

Frequently reported grade 3 or greater adverse events (AEs) in the safety population included hypertension (8% with rezvilutamide vs 7% with bicalutamide), hypertriglyceridemia (7% vs 2%), increased weight (6% vs 4%), anemia (4% vs 5%), and hypokalemia (3% vs 1%). Serious AEs were observed in 28% of patients given rezvilutamide and 21% of patients administered bicalutamide. There were no deaths related to treatment in the rezvilutamide group. However, 1 treatment-related death of unknown specific cause occurred in a patient given bicalutamide.

Overall, this interim analysis demonstrated rezvilutamide plus ADT to significantly improve rPFS and OS vs bicalutamide plus ADT in patients with high-volume, metastatic, hormone-sensitive prostate cancer, and a tolerable safety profile was seen.

1. Gu W, Han W, Luo H, et al. Rezvilutamide versus bicalutamide in combination with androgen-deprivation therapy in patients with high-volume, metastatic, hormone-sensitive prostate cancer (CHART): a randomised, open-label, phase 3 trial. 

. 2022;23(10):1249-1260. doi:10.1016/S1470-2045(22)00507-1

2. A study of SHR3680 in treating patients with hormone sensitive prostate cancer. ClinicalTrials.gov. Updated March 2, 2021. Accessed October 27, 2022. https://clinicaltrials.gov/ct2/show/NCT03520478

Articles

Rezvilutamide is a novel androgen-receptor inhibitor with low blood–brain barrier penetration.

Rezvilutamide/ADT combo boosts survival in hormone-sensitive prostate cancer

Study results presented at the 2022 American Urological Association Annual Meeting showed that the regimen of pembrolizumab (Keytruda) plus cabazitaxel (Jevtana) and gemcitabine had promising early efficacy in heavily pretreated patients with high-risk non–muscle invasive urothelial carcinoma (NMIUC).

In an interview at the meeting, lead study author Vignesh Packiam, MD, urologist, assistant professor of Urology, University of Iowa Hospitals and Clinics, discussed the retrospective analysis.

What is some background of this study examining gemcitabine, cabazitaxel, and pembrolizumab in NMIUC?

 This project is looking at outcomes of a novel regimen for patients with treatment refractory, non-muscle invasive bladder cancer. This is looking at 2 different endoluminal agents, which are gemcitabine, and cabazitaxel in conjunction with an intravenous agent, pembrolizumab

How do gemcitabine and cabazitaxel fit into the care of patients with unresponsive non-muscle invasive bladder cancer?

Our institution has had good success utilizing gemcitabine and docetaxel, which are 2 different chemotherapies used sequentially. It was initially explored for patients with BCG unresponsive disease. Although now with the persistent BCG shortage, we've evaluated this more and more for BCG naive bladder cancer as well. We've noticed that even though the response rate to this agent is very promising, there are some patients that have recurrences to this regimen as well.

We were looking for an effective salvage option for patients who recurred despite receiving gemcitabine/docetaxel. We know from prostate cancer that resistance can eventually form from exposure to docetaxel. In those patients, cabazitaxel is an alternative agent, which has shown to have some efficacy. That was the rationale for utilizing gemcitabine and cabazitaxel within the urinary system.

At the same time, there has been a recent FDA approval of pembrolizumab, which is an intravenous checkpoint inhibitor, although there are concerns about suboptimal long term efficacy. The 1-year complete response for pembrolizumab monotherapy is only 19%, so our hope was with combining these agents, we could develop a more effective treatment regimen for these patients.

This regimen was offered to patients who were heavily pretreated. The median number of prior complete intravascular inductions was for in this cohort. It was a heavily pretreated population of patients who either had too many comorbidities considered to be a reasonable surgical candidate for cystectomy or a patient who had been refusing radical cystectomy. We looked back over the past 2 years for patients who have received this regimen and retrospectively identified 13 patients who received this regimen with a total of 18 treated units. Thirteen were bladder, and 15 renal units, which were which had the presence of carcinoma on side 2 or positive cytology.

What were some of the findings of the initial evaluation?

We found that at initial evaluation, which was a restaging procedure performed at 3 months, there was an 86% complete response rate in the overall cohort with 89% complete response when you're considering each unit separately for the upper tracks and the bladder. The 3-month evaluation was fairly thorough with cystoscopy in situ performed for all patients, random bladder biopsies, prostatic urethral biopsies, and upper tract washings. When we continued surveillance at 6 and 12 months, we noticed that the complete response rate was 79% for patients at 6 months, and 50% for patients at 12 months, which is relatively favorable and promising compared to other agents in this type of paper patient population.

What do your findings tell you about optimal dosing?

We noticed that there was significant bladder toxicity that developed in 5 of these patients. Some of this may have been a result of their heavy pre-treatment history, with alternative regimens used prior to them receiving this treatment regimen. A few patients had to have treatment holidays from the gemcitabine side cabazitaxel to allow their bladders to recover. One patient did require a cystectomy due to end stage bladder symptoms. The optimal dosing is definitely something that we're still exploring.

What can you tell us about the prospective study which will further dive into this topic?

This study has transitioned into a prospective protocol through our cancer center where we are going to more rigorously look for the optimal dosing regimen. It is something that's exciting and I think it's going to help us figure out the efficacy of this regimen and additionally evaluate safety and dosing parameters.

1. Packiam V, McElree I, Steinberg RL, et al. Sequential endoluminal cabazitaxel and gemcitabine with pembrolizumab for docetaxel-unresponsive non-muscle invasive urothelial carcinoma of the upper and lower urinary tracts. Presented at: 2022 American Urological Association Annual Meeting; May 13-16. New Orleans, LA. Abstract PD26-07

Study results presented at the 2022 AUA Annual Meeting showed that pembrolizumab plus cabazitaxel and gemcitabine had promising early efficacy in heavily pretreated patients with high-risk non–muscle invasive urothelial carcinoma.

Dr. Packiam discusses promise of pembrolizumab plus cabazitaxel/gemcitabine in urothelial carcinoma

Sesen Bio announced in a press release that the company has voluntarily paused development in the United States of Vicineum for the treatment of patients with high-risk, Bacillus Calmette-Guerin (BCG)-unresponsive non–muscle invasive bladder cancer (NMIBC).

Vicineum is a locally administered, recombinant fusion protein which works to block protein synthesis to mediate tumor cell death. It is currently being investigated across several solid tumor types.

The basis of the decision comes from thorough reassessment of vicineum, including the incremental development timeline and associated costs for an additional phase 3 clinical trial, following recent discussions with the FDA.

"We have had 4 productive meetings with the FDA since August 2021 and we believe we have a full understanding of the FDA’s evolving position and guidance on the following variables: accelerated versus standard approval, single-arm vs randomized controlled trials, comparative versus non-comparative efficacy end points, and adequate versus less-than-adequate BCG patient populations," said Thomas Cannell, MD, president and chief executive officer of Sesen Bio, in the press release. "We have also recently observed an evolution of the current treatment paradigm in NMIBC, with substantial uptake of intravesical chemotherapy (monotherapy and combination therapy) during the ongoing BCG shortage. In assessing the impact of the regulatory and commercial landscape, we have made the decision to pause the clinical development of vicineum."

Previously, a phase 3 study (NCT02449239) of vicineum was completed. The trial included 134 patients with histologically-confirmed non-muscle-invasive urothelial carcinoma of the bladder, those who had refractory disease after adequate BCG treatment, adequate organ function, and who had received adequate BCG treatment.

In the single-arm study, patients received 30 mg of vicineum in 50 ml of saline, twice a week for a total of 6 weeks followed by the administration of vicineum once a week for 6 weeks. Following the 12-week induction period, patients were administered maintenance vicineum in 50 ml of saline administered once weekly every other week up to 104 weeks.

The primary end point of the study was complete response rate up to 24 months with secondary end points including recurrence rate, event-free survival, number of patients with adverse events (AEs) as a measure of tolerability, changes in echocardiogram, changes in vital signs from baseline, changes in laboratory or physical examination, complete response rate, time to cystectomy, time to disease recurrence, time to progression, progression-free survival (PFS), and overall survival (OS).

Findings revealed that at 3 months, the complete response rate of the evaluable carcinoma in situ (CIS) patients (n = 89) was 40%. The median DoR was 9.4 months (95% CI, 5.1-not evaluable [NE]). Of the patients who responded, 52% remained disease-free for 12 months following the start of treatment. Further, the overall survival rate at 2 years was 96% (95% CI, 92%-100%).

In regard to safety, the majority of the observed AEs were grades 1 and 2, and severe AEs included grade 4 cholestatic hepatitis, grade 5 renal failure, grade 3 acute kidney injury, and grade 2 pyrexia. Only 3% of patients discontinued treatment due to AEs.

Previously, Sesen Bio completed the follow-up stage of a phase 3 clinical trial in the US for the treatment of BCG-unresponsive NMIBC. In February 2021, the FDA accepted a biologics license application (BLA) for vicineum as treatment of BCG-unresponsive NMIBC, granted priority review for the BLA and also set a Prescription Drug User Fee Act (PDUFA) date of August 18, 2021.

The Company also received a complete response letter from the FDA regarding its BLA for vicineum on August 13, 2021, and rejected the request for approval of vicineum as treatment for patients with NMIBC.

With the pause, Sesen Bio continues to assess potential alternatives and intends to seek a partner to aid in further development of vicineum. The activity of vicineum in BCG-unresponsive NMIBC is also being explored at the United States National Cancer Institute in combination with the immune checkpoint inhibitor, durvalumab (Imfinzi).

"We continue to believe that vicineum has benefits for patients and healthcare providers that can be maximized through a company with larger infrastructure, and as such, we intend to find a partner that can execute further development to realize the full potential of vicineum. We now turn our primary focus to the careful assessment of strategic alternatives, which we hope to have completed by the end of the year," added Cannell, in the press release.

1. Sesen bio announces strategic decision to pause clinical development of vicineum™ in the US. News release. Sesen Bio. July 18, 2022. Accessed July 18, 2022. https://yhoo.it/3Pi1za2

2. Shore N, O’Donnell M, Keane T, et al. PD03-02 Phase 3 results of Vicinium in bcg-unresponsive non-muscle invasive bladder cancer. J Urol. 2020; 203(suppl 4). doi: 10.1097/JU.0000000000000823.02

FDA talks have led to a voluntary pause on the development of Vicineum for bladder cancer in the United States.

Development of Vicineum for bladder cancer paused in US

In this interview, Mark C. Markowski, MD, PhD, discusses the abstract, “Sabizabulin has both cytotoxic and cytostatic activity in phase 1b/2 clinical trial of men with metastatic castration resistant prostate cancer (mCRPC) who progressed on androgen receptor targeting agents,” which he shared at the 2022 American Urology Association Annual Meeting.

Can you explain this study of sabizabulin in men with advanced mCRPC?

This is a phase 1b/2 study involving a compound sabizabulin, also called VERU-111, in men with metastatic castration resistant prostate cancer. Sabizabulin is an orally dosed alpha beta tubulin inhibitor. Similar to a taxane chemotherapy, this is found in oral form. We did a dose escalation in phase 1 with about 40 patients. We determined the recommended phase 2 dose, and we conducted the phase 2 study, which was a single arm study, in a similar patient population now looking at efficacy.

What were the methods and design of the study?

It is a phase 1 study initially. We had a dose escalation study, 40 patients were enrolled, and we allowed men with metastatic castration resistant prostate cancer who have had treatment with at least 1 AR targeted therapy and up to 1 taxane chemotherapy for the phase 1 portion of it. It’s a traditional phase 1 study where patients started at a low dose, but we did allow for intrapatient dose-escalation. Patients were initially started at 1 week on 2 weeks off. If they did well, they went up to 2 weeks on, 1 week off, and then eventually daily dosing.

As we worked our way through the dose escalation, we determined that 63 mg per day continuously dosed was going to be the recommended phase 2 dose, and we did not identify a maximum tolerated dose, so we went up to 72 mg and began to see a little bit more GI toxicities. We decided to move down to 63 mg and move that forward. With the phase 2 study, again, that is the 63 mg/day continuously dosed cohort with a similar patient population, but this cohort did not allow for prior chemotherapy. At 63 milligrams, we were looking at efficacy, radiographic progression-free survival, and overall response rates.

Can you discuss the safety and efficacy results found in the trial?

For the phase 1, dose finding study looking at safety, we did find that sabizabulin was pretty safe. It had mild toxicity, grade 1 or 2 primarily, and mostly fatigue and GI toxicities were diarrhea, nausea, and most patients did very well. We had a few grade 3 toxicities in the GI tract. Those were managed well with dose interruption or dose reduction. Again, from the safety perspective, patients did quite well in phase 1.

Then we did see preliminary activity in phase 2. We saw some tumor reduction; we had an objective response rate in the 20% to 30% range. What we found is that patients were on the study for a long time. Progression-free survival was in the range of 9 to 12 months, but we had patients on study for 3 years and that they continue on study. There was some good disease control and in addition to some of the responses in terms of tumor reduction, we saw a lot of disease stability that was durable.

With the toxicity of VERU-111, we saw that it does have similar properties to a taxane chemotherapy, but we did not see those side effects. We don't see the neurotoxicity or the cytopenias that we commonly see with taxanes. It seems to be better tolerated than the taxanes were in terms of the side effect profile. That was an interesting finding and good for patients.

How has this study influenced future research of sabizabulin?

This was the first study that was done in men with sabizabulin. A lot of preclinical work went into this showing some preliminary activity in prostate cancer, breast cancer, pancreatic cancer, etc. There may be other studies and other tumor types coming down the pipeline soon.

The trial we're most interested in right now is the phase 3 VERACITY study [NCT04844749] that was opened based on the results of this trial. Again, that's a phase 3 study. It is randomized with patients with metastatic castration resistant prostate cancer after 1 AR-targeted therapy. They get randomized to the VERU-111 compound, or an alternative AR-targeted agent with the primary end point being radiographic progression-free survival. That study is open and ongoing. We are optimistic to look at efficacy in that study.

What do you believe is next in regard to research in the prostate cancer space?

I think there are a number of different agents coming down the pipeline for prostate cancer that are pretty exciting. There is a whole field of bispecific T-cell engagers and numerous phase 1 and 2 studies looking at that, so that's going to be very exciting. From an immunotherapy perspective, there are a number of studies with bipolar androgen therapy where patients are receiving high doses of testosterone. We're seeing some preliminary activity there, so those are 2 compounds.

Then, there are combination studies with lutetium PSMA. It's exciting to see what we are going to pair with or what we are going to use this VERU-111 compound with, like lutetium PSMA or other therapies. I think there's an endless supply of different drug combinations that we're looking at. I think the future for prostate cancer, particularly in advanced prostate cancer, is bright.

What unmet needs still need to be filled in the mCRPC space?

We need more oral therapies for patients. We have [intravenous] therapies that can be toxic and patients are a little bit reluctant, so oral therapies are needed. Then, we need therapies that get away from the AR-targeting therapy access. A lot of what we do in prostate cancer focuses on hormone therapy and hormone manipulation because it works, but there's a quality-of-life impact to that.

In prostate cancer, maybe early in prostate cancer for local disease or radiation or even biochemical recurrence, there are ways that we can take advantage of biomarkers. If you have a 

 mutation or an NMR deficiency, can we use targeted therapies early on and perhaps delay hormone therapy, but preserve some of that efficacy with PARP inhibitors or immunotherapy? That is a huge unmet need in general and in prostate cancer. Maybe we should think about it more as the quality-of-life impact of lifelong hormone therapy. There are studies that are looking at that, but that's something I would focus on.

What should community oncologists keep in mind when treating patients with this disease?

The tough part about treating advanced cancer is that we don't know exactly how we should cycle our different agents. We are starting to understand that a little bit more, but it's hard on everybody when you treat prostate cancer to know what's the way. What is the first-line, second-line, third-line, fourth? We don't have a clear delineation of therapy and that makes it hard.

I think 1 piece advice for community providers is when you have patients on these therapies, give it some time, even if the PSA is rising. If the PSA is rising, it's okay to keep patients on for a little bit longer, and not to just react reflexively to PSA changes, because what ends up happening is that you cycle through a lot of the drugs that we have, and we don't have an endless supply of treatments, and you end up with fairly refractory resistant prostate cancer with patients that have generally low burden of disease. It's hard to treat those patients because we've gone through them. Patients progress on treatment but give it some time. If you see progression on a scan or clinical progression, maybe that's the indication to move on to other therapies.

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.

“The trial we're most interested in right now is the phase 3 VERACITY study of sabizabulin that was opened based on the results of this trial,” says Mark C. Markowski, MD, PhD.

Jordyn Sava

Articles

Rezvilutamide/ADT combo boosts survival in hormone-sensitive prostate cancer

Dr. Packiam discusses promise of pembrolizumab plus cabazitaxel/gemcitabine in urothelial carcinoma

Development of Vicineum for bladder cancer paused in US

Dr. Markowski highlights potential of sabizabulin in mCRPC