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Case 1: A 68-Year-Old Man with Bone-Predominant Metastatic Castration-Resistant Prostate Cancer (mCRPC)  

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. 

News

FDA accepts BLA for subcutaneous nivolumab in solid tumors

Advancements in genetic testing have opened new doors in the diagnosis and management of prostate cancer.

A key focus of the 2023 Canadian Urological Association (CUA) guideline on genetic testing in prostate cancer is the role of germline genetic testing. This testing offers critical insights into hereditary cancer risk, helping to identify individuals who may benefit from enhanced surveillance, risk-reducing strategies, or tailored therapies.

The updated guideline provides a comprehensive framework for determining who should undergo germline testing, which genes should be analyzed, and how results can influence clinical decision-making. 

In this quiz, the first in a series of 3 based on the guideline, we explore the recommendations for germline genetic testing in prostate cancer management, offering an opportunity to test your understanding of this essential topic!

Editor’s note: This quiz was composed with the aid of artificial intelligence tools

1. Rendon RA, Selvarajah S, Wyatt AW, et al. 2023 Canadian Urological Association guideline: Genetic testing in prostate cancer. 

2023;17(10):314–325. doi:10.5489/cuaj.8588
 

The 2023 Canadian Urological Association guideline emphasizes the importance of germline genetic testing in prostate cancer management. This testing provides valuable insights into hereditary cancer risks, aiding in identifying individuals who may benefit from enhanced surveillance, risk-reducing strategies, or personalized therapies. The guideline offers a detailed framework for determining candidates for germline testing, specifying which genes to analyze, and how the results can guide clinical decisions. This approach aims to optimize patient outcomes through tailored management strategies based on genetic insights.

Test your knowledge of this quiz on the Canadian Urological Association's recommendations for germline genetic testing in prostate cancer management.

Quiz: CUA guidelines on germline genetic testing in prostate cancer

In the era of precision medicine, genomic profiling of tumors has become a cornerstone of advanced cancer care.

The 2023 CUA guideline, titled “2023 Canadian Urological Association guideline: Genetic testing in prostate cancer”, highlights the importance of genomic profiling in prostate cancer, emphasizing its role in informing treatment decisions and prognosis. According to the document, which cites 90 reference documents, by analyzing tumor-specific alterations, genomic profiling allows clinicians to tailor therapies to the unique molecular characteristics of a patient’s disease.

This quiz, our second in a series of 3 on the guideline, will focus on the CUA’s guidance on the use of genomic profiling in prostate cancer, including indications, recommended methodologies, and interpretation of findings. Join us to evaluate your grasp of this pivotal tool in modern oncology!

 2023;17(10):314–325. doi:10.5489/cuaj.8588

Test your knowledge of this quiz on the Canadian Urological Association's recommendations for genomic profiling of tumors in prostate cancer.

Quiz: What CUA guidelines say about genomic profiling of tumors in prostate cancer

Jeremie Calais, MD, PhD, highlights the key components of the report, “Standardized template for clinical reporting of PSMA PET/CT scans.” 

Jeremie Calais, MD, highlights key elements of PSMA-PET reporting template

, highlights the key components of the report, “Standardized template for clinical reporting of PSMA PET/CT scans.” Calais is a nuclear medicine physician at the University of California, Los Angeles.

It's a table, basically, with boxes. It encompasses and contains the miTNM, PROMISE, PRIMARY, RECIP, PSMA-RADS, and E-PSMA concept and criteria all together. On this you have the relevant prostate cancer history, the indication for the scan, primary staging, BCR, PSMA expression assessment before PSMA targeted therapy, some technical parameters that are important, date of scan, the comparison to prior scans, the treatments the patient is on at the time of the scan, [and] how the CT was made. Then some measurement in the salivary glands, in the liver for tumor to background ratio assessments. Then you go by TNM staging. So, you start from the prostate. Both sides, we divided by left, right, apex, midline-based, anterior, posterior. You can check boxes wherever you see uptake or you find suspicious uptake. Number of lesions, seminal vesicles, then the pelvic lymph nodes, extra pelvic lymph nodes, bone metastasis, 1- 2- 3- oligo vs poly, visceral metastasis, the presence or absence of PSMA-negative lesion noted on CT. All that are all summarized into a table that I personally find quite nice to use. These are the main parameters that you can find in these templates.

This transcript was AI generated and edited by human editors for clarity.

“It encompasses and contains the miTNM, PROMISE, PRIMARY, RECIP, PSMA-RADS, and E-PSMA concept and criteria all together,” says Jeremie Calais, MD, PhD. 

We have a question about coding and reporting the UroCuff procedure. Some recommend reporting it with 

) code 51728 with modifier –52 (reduced services), whereas others recommend using 

 code 55899 (Unlisted procedure, male genital system). What are your thoughts on this conundrum?  

The UroCuff test is a noninvasive (no indwelling catheter) natural fill bladder pressure test. Currently, there is no 

 nor Healthcare Common Procedure Coding System code that specifically describes the UroCuff test. This lack of a specific code to report this service can be a burden to both the payer and the provider. Therefore, if this test is considered medically necessary and as such covered by a payer, the path to correct and efficient adjudication may be different for each payer.

Following is a discussion of each option.

Code 51728 (Complex cystometrogram [ie, calibrated electronic equipment]; with voiding pressure studies [ie, bladder voiding profile], any technique)includes both the complex cystometrogram (CMG) and a voiding pressure study. The UroCuff procedure measures bladder voiding pressure but does not provide measurements for the complex CMG. Modifier –52 is defined in 

 as follows: “Reduced Services: Under certain circumstances a service or procedure is partially reduced or eliminated at the physician's discretion. Under these circumstances the service provided can be identified by its usual procedure number and the addition of modifier –52, signifying that the service is reduced. This provides a means of reporting reduced services without disturbing the identification of the basic service.”

Based on the modifier definition, appending the modifier –52 to the 51728 would signify to the payer that a portion of the procedure has been eliminated at the discretion of the physician. Specifically, the physician has elected to perform a voiding pressure study, any technique without a concomitant CMG.

This method of reporting may be preferred by some payers, as it allows for processing of those claims under existing contract and coverage terms and appears to conform with the intended use of the modifier and 

. In their Coding and Advocacy Brief posted on 05-03-2017, the American Urological Association (AUA) examined the UroCuff and issued the following statement: “The Committee determined that 51728-52 is not appropriate to report the voiding pressure study. At this time, the Committee is unaware of a 

 code available to report using a penile pressure cuff for a urethral pressure study. If there are questions, please contact your insurer for possible alternative 

 code or set of codes is agreed upon, we recommend that the agreement is put in writing.”1 (note: link no longer active)

The opinion of the AUA, a premier urologic association, is given significant weight by payers when considering the best way to adjudicate claims. Therefore, payers may require reporting of UroCuff under code 53899 (Unlisted procedure, urinary system) or code 55899 (Unlisted procedure, male genital system).

Medicare and other payers will likely require medical record review regardless of whether you choose to report the voiding pressure study with an unlisted code (53899/55899) or 51728-52, until a coverage policy has been adopted by the payer. Multiple Medicare carriers have issued local coverage articles (LCAs) for some states that direct the use of 55899 with specific verbiage in Box 19 for reporting the UroCuff test. One carrier also included a reimbursement rate in the LCA.

It should be noted as well that regardless of the choice of code 51728-52 or 53899 or 55899, reporting the service will require that Box 19 in the claim form be populated. In these cases, it is recommended that an office use consistent verbiage in Box 19. A payer may use the combination of codes and Box 19 verbiage to develop an adjudication pathway, pricing, and coverage that does not require manual processing and record review for every case.

Given the above background, when determining which code you should use, you must consider your Medicare carrier’s published rules and commercial payer processing policies. Successful urology practices will often establish an internal reporting for UroCuff and assign the revenue cycle management charge release team or, through a series of programmed rules, payer-specific billing protocols. It is imperative to frequently check with the payer regarding reporting and coverage for the UroCuff test as recommended for any other service rendered. Obtain the directions for reporting the UroCuff test in writing, where possible.

Send coding and reimbursement questions to Jonathan Rubenstein, MD, and Mark Painter c/o

Questions of general interest will be chosen for publication. The information in this column is designed to be authoritative, and every effort has been made to ensure its accuracy at the time it was written. However, readers are encouraged to check with their individual carrier or private payers for updates and to confirm that this information conforms to their specific rules.

"When determining which code you should use, you must consider your Medicare carrier’s published rules and commercial payer processing policies," write Jonathan Rubenstein, MD, and Mark Painter. 

UroCuff coding presents a “conundrum” for billers

Investigators have found that the time to testosterone recovery following androgen deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) agonists varies for patients with prostate cancer depending on the length of treatment, baseline testosterone levels, and age.

Findings from the pooled analysis were published in 

“Our findings give patients and doctors valuable insights into what to expect after ADT treatment, helping them make informed decisions about managing side effects and improving long-term outcomes," said senior author Amar U. Kishan, MD, in a news release on the findings.

 Kishan is the executive vice chair of radiation oncology at the David Geffen School of Medicine at the University of California, Los Angeles.

Overall, the study analyzed data from 1444 men who were enrolled across 5 clinical trials in the Meta-Analysis of Randomized Trials in Cancer of the Prostate (MARCAP) Consortium. Among all patients included in the analysis, ADT duration was 4 months for 115 patients, 6 months for 880 patients, 18 months for 353 patients, 28 months for 36 patients, and 36 months for 60 patients. The median survival time was 14.8 years (IQR, 9.3-18), and the median follow-up for survivors was 11 years (IQR, 10-12).

Data showed that the time to noncastrate testosterone recovery and nonhypogonadal testosterone recovery varied by ADT duration. Specifically, the median time to noncastrate testosterone recovery was 8.3 months for those who received 4-month ADT, 5.9 months for 6-month ADT, 5.8 months for 18-month ADT, 14.1 months for 28-month ADT, and 11.7 months for 36-month ADT. The median time to nonhypogonadal testosterone recovery was 20.3 months for those who received 4-month ADT, 8.1 months for 6-month ADT, 11.8 months for 18-month ADT, 27 months for 28-month ADT, and 44.3 months for 36-month ADT.

Further, higher baseline testosterone level and lower age were associated with an increased likelihood for testosterone recovery to noncastrate and nonhypogonadal levels (

 < .001 for both). Age specifically was shown to have large impacts on testosterone recovery.

The unadjusted median effective castration period was 12.8 months, 11.9 months, 23.8 months, 42.2 months, and 47.9 months for those who received ADT for 4 months, 6 months, 18 months, 28 months, and 36 months, respectively. Cox analysis revealed no linear associations between effective castration period and oncological outcomes for any ADT duration.

However, adjusted natural cubic spline analysis did demonstrate a non-linear association between effective castration period and metastasis-free survival (MFS) for patients receiving 6 and 18 months of ADT. According to cubic spline analysis, the optimal effective castration period to achieve MFS benefit was 10.6 months (95% CI 6.0–16.4) for patients receiving 6 months of ADT and 18 months (95% CI 18.0–25.8) for patients receiving 18 months of ADT.

Overall, the authors concluded, “An understanding of [testosterone recovery] kinetics is critical for counseling of men who are starting ADT so that they have realistic expectations regarding the likely time to resolution of ADT-related side effects. Traditional multivariable Cox analyses did not reveal any association between effective castration period and oncological outcomes across the ADT treatment periods. However, there was a nonlinear association between effective castration period and MFS whereby a longer effective castration period was associated with better oncological outcomes. This finding is hypothesis-generating, and future trials should confirm whether a longer ADT duration is needed with GnRH antagonists (which allow more rapid [testosterone recovery]) than with GnRH agonists.”

1. Ong WL, Romero T, Roy S, et al. Testosterone recovery following androgen suppression and prostate radiotherapy (TRANSPORT): A pooled analysis of five randomized trials from the meta-analysis of randomized trials in cancer of the prostate (MARCAP) consortium. 

. 2024:S0302-2838(24)02601-0. doi:10.1016/j.eururo.2024.09.009

2. Study helps predict how long it will take for testosterone to return to normal after prostate cancer treatment. News release. UCLA Health. September 25, 2024. Accessed September 26, 2024. https://www.uclahealth.org/news/release/study-helps-predict-how-long-it-will-take-testosterone

“Our findings give patients and doctors valuable insights into what to expect after ADT treatment, helping them make informed decisions about managing side effects and improving long-term outcomes," says Amar U. Kishan, MD. 

Jose De La Cerda III, MD, MPH

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