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Benjamin P. Saylor is associate editor of Urology Times, an Advanstar Communications publication.

The approval is supported by findings from the phase 3 ENVISION trial.

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In this article, an expert addresses the most common issues that come up with patients that may make them harder to deal with and solutions that may help a provider.

Strategies for dealing with difficult patients

The FDA has accepted a new drug application (NDA) for zoliflodacin, an investigational first-in-class, single-dose, spiropyrimidinetrione oral antibiotic for the treatment of adult and pediatric patients 12 years and older with uncomplicated gonorrhea, Innoviva Specialty Therapeutics announced in a news release.

The Prescription Drug User Fee Act (PDUFA) target action date for the application is December 15, 2025.

Zoliflodacin is an oral antibiotic that inhibits type II topoisomerase, a bacterial enzyme that plays a key role in bacterial function and reproduction. According to the company, “If approved, zoliflodacin would be the first new antibiotic for treating gonorrhea in decades.”

The FDA has also granted a Qualified Infectious Disease Product designation to zoliflodacin, which enables the agent to benefit from priority review and market exclusivity.

“Today’s acceptance of the zoliflodacin NDA marks significant progress toward delivering health care providers with a potential new oral treatment option for uncomplicated gonorrhea, including infections caused by drug-resistant strains,” said David Altarac, MD, Chief Medical Officer of Innoviva Specialty Therapeutics, in the news release.

 “We look forward to working closely with the FDA during its review and, if approved, we are committed to expediting the availability of zoliflodacin to patients in the U.S.”

The NDA for zoliflodacin is supported by data from several clinical trials conducted through a collaboration with the Global Antibiotic Research & Development Partnership (GARDP). This portfolio of studies includes a pivotal phase 3 trial (NCT03959527) that evaluated zoliflodacin vs a standard of care (SOC) regimen (500 mg ceftriaxone intramuscular plus 1g oral azithromycin) in patients with uncomplicated gonorrhea.

Overall, the trial met its primary end point by demonstrating that zoliflodacin was non-inferior to the SOC regimen regarding microbiological response at the urogenital site at the test of cure visit (6 +/- 2 days following treatment). Specifically, the microbiological cure rate was 90.9% in the zoliflodacin arm vs 96.2% in the ceftriaxone/azithromycin arm, representing a difference of 5.3% (95% CI, 1.4% to 8.7%) across patients in the micro-intent-to-treat (ITT) population.

The 2 cohorts also demonstrated comparable results on the trial’s secondary end point of microbiological response at extragenital (rectal or pharyngeal) sites. Specifically, at pharyngeal sites, the cure rate was 79.2% in the zoliflodacin arm vs 78.6% in the ceftriaxone/azithromycin arm (difference, -0.67%; 95% CI, -20.8 to 16.3). At rectal sites, the cure rate was 87.3% and 88.6%, respectively (difference, 1.23%; 95% CI, -14.4 to 12.6).

Zoliflodacin was generally well-tolerated in the trial. Treatment-emergent adverse events (TEAEs) occurred in 46.2% of patients in the zoliflodacin arm vs 46.4% of patients in the ceftriaxone/azithromycin arm. The most common TEAEs in the zoliflodacin arm included headache (9.9%), neutropenia (6.8%), and leukopenia (3.9%).

There were no deaths or serious adverse events reported in either arm.

In total, the phase 3 trial included 930 patients with uncomplicated gonorrhea, including patients living with HIV. The study enrolled participants across 16 clinical trial sites in the US, Belgium, the Netherlands, South Africa, and Thailand.

According to Innoviva, the phase 3 study was “the largest clinical trial ever conducted for a new treatment against gonorrhea infection.”

Those enrolled in the study were randomly assigned 2:1 to receive 3 g single-dose, oral zoliflodacin (n = 621) or to 500 mg ceftriaxone intramuscular plus 1g oral azithromycin (n = 309). The primary end point was microbiological cure by culture at urogenital sites in the micro-ITT populations, with a non-inferiority margin of 12%. The trial’s secondary end point was microbiological cure at extragenital sites.

“This important milestone demonstrates the crucial role that public-private partnerships can play in tackling the escalating global antimicrobial resistance crisis,” said Manica Balasegaram, Executive Director of GARDP, in the news release.

 “If zoliflodacin is approved, this collaboration paves the way for millions of people across the world to get access to a potentially powerful new drug to treat multidrug-resistant gonorrhea.”

1. Innoviva Specialty Therapeutics receives FDA New Drug Application acceptance for zoliflodacin, a first-in-class oral antibiotic for uncomplicated gonorrhea in adults. News release. Innoviva Specialty Therapeutics. Published online and accessed June 10, 2025. https://innovivaspecialtytherapeutics.com/innoviva-specialty-therapeutics-receives-fda-new-drug-application-acceptance-for-zoliflodacin-a-first-in-class-oral-antibiotic-for-uncomplicated-gonorrhea-in-adults/

2. FDA Grants Priority Review for Zoliflodacin New Drug Application for the Treatment of Uncomplicated Gonorrhea and Assigns Target PDUFA Date of December 15, 2025. News release. Innovia Specialty Therapeutics, Inc. Published online and accessed June 12, 2025. https://www.businesswire.com/news/home/20250612432209/en/FDA-Grants-Priority-Review-for-Zoliflodacin-New-Drug-Application-for-the-Treatment-of-Uncomplicated-Gonorrhea-and-Assigns-Target-PDUFA-Date-of-December-15-2025 

3. Luckey A, Broadhurst H, Daram P, et al. Oral zoliflodacin is non-inferior to a combination of ceftriaxone and azithromycin for treatment of uncomplicated urogenital gonorrhoea: results of a large global Phase 3 randomised controlled trial. Presented at: European Society of Clinical Microbiology and Infectious Disease Global Congress. April 27-30, 2024. Barcelona, Spain. https://gardp.org/wp-content/uploads/2024/04/Zoli001-Topline-ECCMID2024_final_V1.0_23Apr2024_.pdf

The NDA is supported by a pivotal phase 3 trial of zoliflodacin vs ceftriaxone plus azithromycin in patients with uncomplicated gonorrhea. 

News

FDA accepts new drug application for zoliflodacin for uncomplicated gonorrhea

Dr. De La Cerda provides an overview of a patient case involving a 68 year-old male presenting with severe back pain, with an analysis of the clinical presentation, workup, and medical history.

Bone Predominant mCRPC Patient Case

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The FDA has accepted a Biologics License Application (BLA) seeking approval of nivolumab (Opdivo) co-formulated with Halozyme’s proprietary recombinant human hyaluronidase (rHuPH20), or subcutaneous nivolumab, for the treatment of patients with all previously approved solid tumor indications for nivolumab as a monotherapy, monotherapy maintenance following completion of combination therapy with nivolumab plus ipilimumab (Yervoy), or in combination with chemotherapy or cabozantinib (Cabometyx).

Nivolumab is currently approved under several indications, including in combination with ipilimumab for the first-line treatment of patients with intermediate- or poor-risk advanced renal cell carcinoma (RCC), in combination with cabozantinib for the first-line treatment of patients with advanced RCC, for the treatment of patients with advanced RCC who have received prior anti-angiogenic therapy, and in combination with cisplatin and gemcitabine for the first-line treatment of patients with unresectable or metastatic urothelial carcinoma.

The FDA is set to have a decision regarding the subcutaneous nivolumab formulation on or by December 29, 2024.

 According to a news release from Bristol Myers Squibb,

 approval of the formulation would make it the first and only subcutaneously administered PD-1 inhibitor.

“We believe subcutaneous nivolumab has the potential to make a significant difference in the lives of patients, which is reinforced by the FDA’s acceptance of our application,” said Gina Fusaro, PhD, vice president, global program lead, Bristol Myers Squibb, in the news release.

 “Opdivo is a foundational PD-1 inhibitor approved for many different types of cancer, and our continued investment in research that puts patients first remains a priority. If approved by the FDA, the subcutaneous administration of nivolumab would provide patients and their physicians with a new option that delivers the same well-known benefits as IV Opdivo but with the improved convenience of an injection administered in 3 to 5 minutes rather than a 30-to-60-minute infusion.”

The BLA submission is supported by findings from the phase 3 CheckMate-67T trial (NCT04810078), in which subcutaneous nivolumab met the study’s co-primary end points by demonstrating noninferiority to intravenous (IV) nivolumab regarding time average nivolumab serum concentration over 28 days (C

; geometric mean ratio [GMR}, 2.098; 90% CI, 2.001-2.200) and minimum serum concentration at a steady state (C

Data from the study, which were presented at the 2024 American Society of Clinical Oncology Genitourinary Cancers Symposium in San Francisco, California,

 also showed that subcutaneous nivolumab demonstrated noninferiority to IV nivolumab in the key powered secondary end point of objective response rate (ORR). Specifically, the subcutaneous arm demonstrated an ORR of 24.2% (95% CI, 19.0-30.0) per blinded independent central review (BICR), compared with 18.2% (95% CI, 13.6-23.6) in the IV arm.

The safety profile for subcutaneous nivolumab was consistent with that of the IV formulation. Among patients who received the subcutaneous formulation, 8.1% experienced injection-site reactions, with all being low-grade and transient. Deaths due to study drug toxicity occurred in 3 patients in the subcutaneous arm and 1 patient in the IV arm. Most deaths that occurred during the study were due to disease progression.

In total, the phase 3, open-label CheckMate-67T trial enrolled 495 patients with advanced or metastatic ccRCC who had received prior systemic therapy. Patients were randomly assigned 1:1 to receive 1200 mg subcutaneous nivolumab plus rHuPH20 every 4 weeks (n = 248) or to 3 mg/kg IV nivolumab every 2 weeks (n = 247) for up to 2 years of treatment or until disease progression, unacceptable toxicity, withdrawal, or death.

The co-primary pharmacokinetic end points for noninferiority testing were C

 of subcutaneous nivolumab vs IV nivolumab. The key secondary end point was ORR per BICR.

Final completion of the CheckMate-67T study is expected in January 2026.

1. U.S. Food and Drug Administration accepts Bristol Myers Squibb’s application for subcutaneous nivolumab (nivolumab and hyaluronidase). News release. Bristol Myers Squibb. May 6, 2024. Accessed May 7, 2024. https://news.bms.com/news/corporate-financial/2024/U.S.-Food-and-Drug-Administration-Accepts-Bristol-Myers-Squibbs-Application-for-Subcutaneous-Nivolumab-nivolumab-and-hyaluronidase/default.aspx

2. Bristol Myers Squibb announces updated action date by the U.S. Food and Drug Administration for subcutaneous nivolumab (nivolumab and hyaluronidase). News release. Published online and accessed May 21, 2024. https://investors.bms.com/iframes/press-releases/press-release-details/2024/Bristol-Myers-Squibb-Announces-Updated-Action-Date-by-the-U.S.-Food-and-Drug-Administration-for-Subcutaneous-Nivolumab-nivolumab-and-hyaluronidase/default.aspx

3. George S, Bourlon TB, Chacon MR, et al. Subcutaneous nivolumab (NIVO SC) vs intravenous nivolumab (NIVO IV) in patients with previously treated advanced or metastatic clear cell renal cell carcinoma (ccRCC): Pharmacokinetics (PK), efficacy, and safety results from CheckMate 67T. 

4. A study of subcutaneous nivolumab versus intravenous nivolumab in participants with previously treated clear cell renal cell carcinoma that is advanced or has spread (CheckMate-67T). ClinicalTrials.gov. Last updated March 1, 2024. Accessed May 7, 2024. https://clinicaltrials.gov/study/NCT04810078

The FDA is set to have a decision regarding the subcutaneous nivolumab formulation on or by December 29, 2024. 

FDA accepts BLA for subcutaneous nivolumab in solid tumors

The first patient has been dosed in a phase 1 trial (NCT06801236) investigating the novel CYP11A1 inhibitor ACE-232 in patients with metastatic castration-resistant prostate cancer (mCRPC), Acerand Therapeutics announced in a news release.

According to the company, ACE-232 is a “highly potent and selective small-molecule inhibitor of CYP11A1, a key adrenal enzyme involved in the first and rate-limiting step of steroid hormone biosynthesis.”

In preclinical studies, ACE-232 demonstrated superior potency, efficacy, and pharmacokinetic properties compared with other CYP11A1 inhibitors. The data, which were presented at the 2025 American Association for Cancer Research Annual Meeting in Chicago, Illinois, also showed that ACE-232 was well-tolerated and demonstrated efficacy against preclinical models resistant to current therapies, including abiraterone acetate (Zytiga) and enzalutamide (Xtandi), Acerand reported.

The FDA granted an investigational new drug clearance to the agent in January 2025 to initiate the first-in-human trial.

“I would like to congratulate the Acerand team, the research staff, and the first patient for helping us to reach this important milestone,” said principal investigator Emmanuel S. Antonarakis, MD, in the news release.

 Antonarakis is the director of genitourinary oncology at the Masonic Cancer Center at the University of Minnesota, Minneapolis.

In total, the open-label phase 1 trial plans to enroll 67 adult patients across clinical trial sites in the US and Canada.

Patients are eligible for enrollment if they have mCRPC with ongoing androgen deprivation therapy or have bilateral orchiectomy, an ECOG Performance Status of 0 or 1, a life expectancy of at least 6 months, and adequate organ and bone marrow function. Patients must have also underwent at least 1 prior line of therapy with a novel hormonal agent and taxane-based chemotherapy in the castration-resistant or hormone-sensitive setting.

The study is being conducted in 2 parts: a dose escalation and dose optimization phase. In phase 1, the investigators will assess the safety, tolerability, pharmacokinetic profile, and pharmacodynamics in patients following treatment with ACE-232. Phase 1 also seeks to establish a maximum tolerated dose, if applicable. In phase 2, patients with androgen receptor gene alterations will receive ACE-232 at 2 different dose levels with the goal of establishing the recommended phase 2 dose.

For the study, patients will receive ACE-232 tablets orally as a continuous regimen with dexamethasone and fludrocortisone (Florinef) until disease progression, unacceptable toxicity, or study withdrawal.

The primary end points for the study are the number of patients experiencing an adverse event (AE) or serious AE, the number of patients experiencing a dose-limiting toxicity, and the establishment of a maximum tolerated dose and recommended phase 2 dose. Secondary outcome measures include pharmacokinetic measures, prostate-specific antigen response, objective response rate, duration of response, radiographic progression-free survival, overall survival, and blood concentration of steroid hormone.

The investigators are also seeking to assess the association between gene aberrations in circulating tumor DNA and tumor response to treatment as an exploratory end point.

Final completion of the trial is expected in August 2028.

1. Acerand Therapeutics initiates first-in-human phase I clinical trial of ACE-232, a novel CYP11A1 inhibitor for advanced prostate cancer. News release. Acerand Therapeutics. June 4, 2025. Accessed June 9, 2025. https://www.acerand.com/nw_20250604.html

2. Acerand announces promising ACE-232 preclinical data to be presented at the 2025 AACR Meeting. News release. Acerand Therapeutics. April 10, 2025. Accessed June 9, 2025. https://www.acerand.com/nw_20250410.html

3. Phase 1 study of ACE-232 to treat patients with metastatic castration-resistant prostate cancer. ClinicalTrials.gov. Last updated May 18, 2025. Accessed June 9, 2025. https://clinicaltrials.gov/study/NCT06801236

A phase 1 trial has commenced for ACE-232, a novel CYP11A1 inhibitor, in patients with metastatic castration-resistant prostate cancer (mCRPC). ACE-232 has shown superior potency and efficacy in preclinical studies, particularly against models resistant to current therapies. The trial, involving 67 patients across the US and Canada, will assess safety, tolerability, and pharmacokinetics, aiming to establish a maximum tolerated dose. The study will also explore the relationship between gene aberrations in circulating tumor DNA and treatment response, with completion expected by August 2028.

In preclinical studies, ACE-232 demonstrated superior potency, efficacy, and pharmacokinetic properties compared with other CYP11A1 inhibitors. 

Phase 1 study launches for novel CYP11A1 inhibitor for mCRPC

Radical cystectomy should continue to have an important role in the management of patients with recurrent high-grade non–muscle invasive bladder cancer (NMIBC), according to 12-month results from the CISTO study (NCT03933826).

2025 American Urological Association (AUA) Annual Meeting

 in Las Vegas, Nevada by John L. Gore, MD, MS, an adjunct professor of surgery at the Fred Hutchinson Cancer Center at the University of Washington in Seattle.

“We previously demonstrated in a broad survey of over 1000 patients in the Bladder Cancer Advocacy Network Patient Survey Network that the highest priority for patients with non–muscle invasive bladder cancer is to better understand how to make decisions about the timing of radical cystectomy as well as how to balance that with other treatments when their bladder cancers fail BCG,” Gore explained during the presentation. “We demonstrated in a comprehensive systematic review that limited evidence is available to help clinicians make better decisions for their patients with recurrent high-grade non–muscle invasive bladder cancer.”

To that end, the investigators launched the CISTO study to assess outcomes with intravesical therapy vs radical cystectomy in this patient population. The trial was conducted as a prospective observational cohort study.

“Our engagement with patients in the Bladder Cancer Advocacy Network informed the CISTO study design, as patient responses told us that a randomized control trial would not be feasible, given that only 11% of patients would be willing to be randomized in a comparison of radical cystectomy—a morbid, large-scale surgery—with bladder-sparing treatments.”

In total, the trial included 371 patients in the bladder-sparing therapy arm and 199 patients in the surgery arm.

Gore noted, “Our treatment groups were balanced by sex, race and ethnicity, and comorbidity burden. Patients undergoing radical cystectomy were younger, were more likely to be partnered, were less likely to live in an urban area, and had higher cancer severity as measured by a greater proportion of patients with T1 disease or concomitant CIS.”

On the study’s primary end point of 12-month physical functioning, the data showed no significant difference between the study cohorts.

Gore added, “[In] data within subgroups of patients with concomitant CIS and among individuals who were not partnered at enrollment, physical functioning was better in the radical cystectomy arm.”

Patients in the radical cystectomy arm also demonstrated improved global health compared with those in the bladder-sparing therapy arm. Additionally, patients in the radical cystectomy arm showed favorable emotional functioning scores vs those in the bladder-sparing therapy arm, which included lower levels of depression and anxiety.

Scores for financial difficulties and financial toxicity also favored the radical cystectomy arm.

Longitudinal physical functioning scores were largely comparable between both cohorts.

Gore reported, “[Our data showed] similar physical functioning at enrollment, an expected decline in physical functioning at 3 months after radical cystectomy given the large scale of the surgery, but a recovery trajectory where physical functioning is similar between treatment groups by 6 months. This was true across the entire cohort, as well as among those patients over 75 years of age, demonstrating that the finding of noninferior physical functioning held true for older CISTO study participants as well.”

However, patients who underwent radical cystectomy demonstrated worse urinary health scores compared with those who received bladder-sparing therapy. Both sexual quality of life and bowel quality of life scores were also worse among patients who underwent radical cystectomy.

Regarding clinical outcomes, data showed comparable bladder cancer-specific survival rates between the 2 arms. Specifically, the rate was 96% in the radical cystectomy arm vs 99% in the bladder-sparing therapy arm (aRR, 0.98; 95% CI, 0.96 to 1.01). However, the radical cystectomy cohort demonstrated a significant improvement in 12-month recurrence-free survival (RFS). In the radical cystectomy arm, RFS was 96%, compared with 67% in the bladder-sparing therapy arm (aRR, 0.12; 95% CI, 0.06 to 0.27).

Gore also added, “Twelve-month progression-free survival was significantly better in the bladder-sparing therapy arm, although this was mostly driven by pathologic upstaging for patients in the radical cystectomy arm.”

The CISTO study remains ongoing to assess longer-term outcomes.

“Radical cystectomy, as demonstrated by the CISTO study, has and should continue to have an important role in the management of recurrent high-grade non–muscle invasive bladder cancer,” Gore concluded during the presentation. “These are outcomes that do inform patient and clinician decision-making, and we have obtained additional NCI [National Cancer Institute] funding that will support ascertaining longer-term patient-reported and clinical outcomes.”

1. Gore JL, Wolff EM, Nash MG, et al. Radical cystectomy versus bladder-sparing therapy for recurrent high-grade non-muscle invasive bladder cancer: Results from the comparison of intravesical therapy and surgery as treatment options (CISTO) study. 

2025;213(5S):e3. doi:10.1097/01.JU.0001111604.90306.91.05

The CISTO study highlights the significant role of radical cystectomy in managing recurrent high-grade non–muscle invasive bladder cancer (NMIBC). Conducted as a prospective observational cohort study, it compared outcomes of radical cystectomy with bladder-sparing therapy. Results showed no significant difference in 12-month physical functioning between the groups, but radical cystectomy patients had better global health and emotional functioning. However, they experienced worse urinary, sexual, and bowel quality of life. Radical cystectomy showed improved recurrence-free survival, while bladder-sparing therapy had better progression-free survival. The study continues to assess long-term outcomes.

Twelve-month physical functioning scores were comparable between the radical cystectomy arm and the bladder-sparing therapy arm.

Amanda Hill, JD

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