Leonardo da Vinci is credited with having drawn the world’s first robot in 1495. This device was a complex suit of armor with flexible joints controlled by a series of pulleys and is the same basic concept used by the current iteration of Intuitive Surgical’s da Vinci robotic surgical system.

Urology, as a field, has been at the forefront of the utilization of this technology since its inception. Robot-assisted laparoscopic prostatectomy is almost synonymous with robotic technology. Nearly every hospital system with a robotic platform has at least one high-volume genitourinary oncologist recording the most time on the console.

The most familiar robots used in genitourinary oncologic surgery are known as online robotic systems. These devices were designed to replicate, in real time, a surgeon’s hand movements. Interestingly, the first non-microscopic surgical robots were designed for use by the U.S. Department of Defense.

 The concept was a mobile armored operative suite that could be manned by surgeons at the rear of the battle. This setup would keep them out of harm’s way, with the hope of minimizing casualties and protecting surgeons. Although we now associate robotics with safe, sterile operative suites, this could not have come to fruition without the U.S. military.

Thanks to urologic pioneers and an ongoing push for a minimally invasive approach in an ever-growing breadth of surgical applications, the future looks bright for robotics in genitourinary oncology.

Mani Menon, MD, is an American surgeon whose pioneering work laid the foundation for modern robotic cancer surgery. In 1997, Dr. Menon was recruited to become chairman of urology at Henry Ford Hospital. This transition of power led to Henry Ford Hospital’s urology department receiving a $20 million donation from the Vattikuti Foundation, effectively establishing the Vattikuti Urology Institute.

This financial backing freed Dr. Menon to explore minimally invasive techniques and establish robotic prostatectomy. He has performed nearly 4,000 robotic prostatectomies and is considered a world authority on the use of robotic surgery for prostate cancer.

Intuitive was founded in 1995. World-renowned experts in telerobotic technology, human-machine interfaces, and minimally invasive surgical techniques laid the groundwork for surgical robots. Intuitive launched the first da Vinci surgical system in 1999; it became the first robot-assisted surgical system for laparoscopic surgery cleared by the FDA in 2000.

As of 2018, there was an installed base of 4,986 units worldwide-close to 3,000 in the United States. Per the company website, more than six million minimally invasive surgeries have been completed using da Vinci technology as of 2018. Additionally, more than 18,000 scientific articles on Intuitive surgical products and procedures have been published.

The da Vinci Si System was launched in 2009 and is the first model to offer dual-surgeon console capability, thus supporting training and collaboration during minimally invasive surgery. Additionally, this model also incorporated high-definition 3D vision.

In 2014, the da Vinci Xi System had broader capabilities than earlier generations. These included the ability to perform multiquadrant surgeries or procedures where instruments must be able to reach up and down across the abdomen or chest. The Xi was the first system to have an overhead instrument arm configuration, allowing anatomic access from virtually any position. It also incorporated the ability to attach the endoscope to any arm, as well as the greatest range of motion with a longer instrument shaft designed to give surgeons greater operative reach.

Announced in 2017, the da Vinci X is the newest Intuitive product on the scene. It is advertised as a cost-conscious option with arm architecture similar to that of the Xi, with the goal of placing even more units into hospitals where price had previously precluded purchase.

The da Vinci SP is a new member of the family, designed for the narrowest access surgery. With the SP, a single arm delivers three multijointed instruments and a fully wristed 3-D high-definition camera for visibility and control in narrow surgical spaces. At present, the potential benefits of laparoendoscopic single-port surgery include improved cosmesis, reductions in wound infection rates, quicker recovery, and reduced postoperative hernia. However, these benefits cannot be fully evaluated until the size of single-site trocar incisions and tools is optimally miniaturized.

General limitations for robotic surgical platforms include high start-up costs and setup times involved with individual surgeries. The da Vinci system uses proprietary software that cannot be modified by physicians, thereby limiting the freedom to adjust the operation system. Furthermore, a $2 million cost places it beyond the reach of many institutions. For example, the Si version costs on average slightly under $2 million, in addition to several hundred thousand dollars of annual maintenance fees.

Another large drawback is the lack of haptic feedback, requiring the use of visual cues compared with more traditional attention and texture techniques. This can be dangerous and has also led to a reported steep learning curve for robotic surgery.

One of the greatest strengths of robotic technologies is increased manual dexterity along with tremor-filtering functions. Additional benefits include the ergonomic control stations and the ability to perform complex surgery in a solo fashion by using more than two arms at once.

As laparoscopy and robotic surgery continue to gain popularity, a continued push to develop laparoendoscopic single-port surgery has followed. Engineers and medical technology companies continue to develop products with the ultimate goal of natural orifice transluminal endoscopic surgery-a transvaginal cystectomy/neobladder with no abdominal incisions. Although Intuitive continues to dominate the field, there are several competing systems worth noting.

The Senhance Surgical System (TransEnterix) currently used in some gynecologic procedures has multiple manipulator arms controlled from a remote station. One main feature of this platform is that it provides actual tactile haptic feedback so surgeons can feel the tension they are applying at the distal end of their endoscopic instruments. Interestingly, the Senhance system also employs eye-tracking software that allows the surgeon to naturally focus on tissue of interest without having to redirect the endoscopic camera.

Competing in the single-port surgical space is the Flex Robotic System (Medrobotics Corp.). This is not currently approved for urologic procedures but is used in oral and head and neck surgery. Flex allows surgeons the freedom to manipulate around target anatomy by defining a nonlinear path to surgical sites. The operator is able to perform this technique by advancing a flexible outer sheath through which the inner channel instruments are deployed.

Although not currently FDA approved, SPORT (Single-Port Orifice Robotic Technology, Titan Medical Inc.) features a design with a collapsible system that can be inserted through a 25-mm incision. In preclinical testing, it has been used to successfully complete a nephrectomy in animal models.

Anecdotally, one cannot discuss future robotic technologies without mentioning Verb Surgical (Verb J&J/Alphabet), a company founded in partnership with Google. Although little information is available, the prototype has been reported to combine robotics and data-driven machine learning to reduce surgical costs and expand the use to a larger array of surgeons. The company’s stated goal is to “democratize surgery,” an attempt to not just create a new surgical platform but also truly develop a new category of digital surgery.

As exciting as these newer platforms may sound, it will be some time before we see competitors in the commercial market. Regardless, the prevalence of robotic platforms will increase in smaller communities and other countries. Contemporary literature has demonstrated that the use of partial nephrectomy has increased and open radical nephrectomy has decreased since the adoption of the robot.

 This trend will continue not only in kidney cancer but also in other subspecialties.

In tertiary referral centers, we will continue to see more and more difficult procedures performed robotically as experience continues to grow. In addition to the now standardized oncologic surgeries, we will see more complex reconstructions and vascular surgeries performed by a robot. In October 2019, a team from the Glickman Urological & Kidney Institute in Cleveland successfully performed the world’s first robotic single-port kidney transplantation.

 Small case series are beginning to come out presenting radical nephrectomy with inferior vena cava thrombectomy up to a level IV thrombus.

Robotic surgical platforms, as evidenced by the adoption of the da Vinci, have had a rapid and far-reaching impact on the performance of minimally invasive surgical procedures in urologic surgery as well as in other disciplines. Further developments in robotics will continue to enhance this performance and promise to improve outcomes in a wide swath of surgical fields. Urologic surgery has been a leader in robotic surgery development, and this technological revolution in the operating room continues to redefine urology and all of surgery.

All data seem to expect this trend to continue accelerating. It is projected that the global market for surgical robots will experience a compound annual growth rate of 10.4%, from $3.9 billion in 2018 to $6.5 billion by 2023.

Military Robotic Combat Casualty Extraction and Care. Surgical Robotics

2. Menon M, Tewari A. Robotic radical prostatectomy and the Vattikuti Urology Institute technique: an interim analysis of results and technical points. 

3. Leslie S, Goh A, Gill I. Partial nephrectomy-contemporary indications, techniques and outcomes. 

4. Cleveland Clinic first in the world to perform robotic single-port kidney transplant. Accessed 2/6/20. Cleveland Clinic website. (

5. Wang B, Huang Q, Liu K, et al. Robot-assisted level III-IV inferior vena cava thrombectomy: initial series with step-by-step procedures and 1-yr outcomes. 

6. Surgical Robots Market by Product & Service (Instruments & Accessories, Systems, Service), Application (Urological Surgery, Gynecological Surgery, Orthopedic Surgery), End User (Hospitals, Ambulatory Surgery Centers) - Global Forecasts to 2025. Markets and Markets. Accessed 2/6/20. 

Articles

The breadth of applications will widen as the number of new platforms grows, according Joshua Calvert, MD, MPH.

Robotics in GU oncology: Current status, future directions

 is chief clinical urologist officer, Integra Connect, West Palm Beach, FL, and clinical associate professor of urology, Vanderbilt University School of Medicine, Nashville, TN.

Prostate cancer is a clinically heterogenous disease with variability in progression once diagnosed, ranging from the very indolent cases that may require no therapy to patients who present with de novo metastasis. In 2019, there were approximately 174,650 newly diagnosed prostate cancer cases in the United States and a cancer-specific mortality of 31,620 directly attributable to the disease or 5.2% of all cancer deaths.

A number of newer therapies (all mechanistically different) and treatment regimens have been approved for the management of both patients with metastatic castration-sensitive prostate cancer (mCSPC) and metastatic castration-resistant prostate cancer (mCRPC). A unique dynamic progressive model estimates the incidence of these two subsets may approach 42,970 patients in 2020.

Unfortunately, despite the availability of superior agents, optimal sequences or a combination of these oncolytics have yet to determined, as there are no predictive biomarkers to inform the provider what is the most ideal initial line of therapy (LOT) and as patients progress, what will be the most appropriate next LOT. What makes this situation even more challenging is that these newer therapies, as well as those that we anticipate will be approved in 2020 and beyond, are targeted for molecular drivers of prostate cancer. For the patient with mCSPC or mCRPC, how can we best determine the initial and subsequent LOTs, given the limitations of the monotherapy registration trials?

A number of key genomic mutations have been consistently identified in patients with prostate cancer (hormone naive and mCRPC). These mutations include gene fusion/chromosomal rearrangements 

 androgen receptor (AR) amplification, inactivation of tumor suppressor genes (

/PI3-K/AKT/mTOR, TP53, Rb1), and oncogene activation (

 More significantly, defects in DNA repair appear to be central in increasing one’s susceptibility to malignant transformation.

It is critical to patient management that we determine whether these mutations are inherited (germline) or acquired (somatic). Germline mutations are changes in DNA that are present in the patient’s reproductive cells (sperm or ovum) and are thus passed from generation to generation and will be identified in every cell of the body. Therefore, germline testing can be conducted with just a swab from the mouth, saliva, or blood from the patient. There are many companies in the United States that currently offer germline testing.

It is paramount that in order to obtain the most comprehensive analysis and report, genetic testing through next-generation sequencing in a diagnostic laboratory is mandatory. This type of testing should be compared with many of the direct-to-consumer tests that are currently marketed to patients. The testing platforms deployed by many of these companies are much less robust and often include a very limited number of known genetic mutations in their panels.

For example, thousands of identified BRCA mutations have been identified, but only a handful may be tested in some of these direct-to-consumer testing kits. This situation can lead to an unacceptable number of studies with false-negative results and should not be used for clinical decision-making.

Acquired or somatic mutations can be defined as any alteration in DNA that occurs after conception. These can occur in any cell of the body (except the reproductive cells) and usually arise as a result of exogenous or environmental exposures, such as tobacco smoking or UV radiation. Therefore, somatic testing requires next-generation sequencing of cells extracted from the tumor itself and cannot be performed by using a sample of saliva or blood.

Pritchard and colleagues were among the first to demonstrate the value of assessing inherited genetic changes in prostate cancer. Among 692 patients with metastatic prostate cancer, they examined the prevalence of mutations in 20 DNA repair genes.

 Mutations were identified in 82 men (11.8%) with significant geographic heterogeneity, even among these recognized cancer centers (prevalence of 8.8% in patients treated at the University of Washington and 18.5% in those treated at Memorial Sloan Kettering), potentially reflecting referral biases. Subsequently, Castro et al found a prevalence of germline DNA damage repair gene mutations of 16.2% in patients with mCRPC.

Unlike other disease states in which commonly identified germline mutations may be actionable, actionable germline mutations are relatively uncommon in patients with prostate cancer. Nicolosi and colleagues found that actionable mutations were identified in 1.74% of their study cohort with a diverse patient population.

 In previous analyses, Robinson et al reported clinically actionable pathogenic germline mutations in 8% of 150 patients with mCRPC, in contrast to clinically actionable aberrations in the AR in 63% and aberrations in other cancer-related genes in 65% of patients.

 It is likely not surprising that actionable underlying germline mutations would be more common in a cohort with more advanced prostate cancer.

In patients with regional or metastatic prostate cancer, somatic tumor testing may also be considered on the basis of the observation that nearly 90% of men have potentially actionable mutations at the tumor level, whereas only a relatively small proportion of men would have actionable germline mutations (approximately 9% of patients with mCRPC, according to the National Comprehensive Cancer Network). In these patients, testing may be undertaken for somatic homologous recombination repair (HRR) gene mutations (eg, 

) and for microsatellite instability (MSI) or mismatch repair (MMR).

In patients with advanced prostate cancer, identification of underlying germline mutations may guide treatment selection to determine the most appropriate next LOT, especially in those who have progressed through multiple lines of prior therapy, including AR signaling agents. Patients with identified MSI-high status, defects in DNA MMR genes, or 

 biallelic loss may respond to checkpoint inhibition therapy.

Pembrolizumab (KEYTRUDA), an FDA-approved PD-1 inhibitor, is the first immunotherapy to win approval in a tumor-agnostic manner and not based on organ type. Further, patients with mutations in HRR genes (including 

, and genes that cause Fanconi anemia) may be better suited for treatment with PARP inhibitors, many of which are in ongoing phase III trials with expected approval in 2020.

Finally, patients with DNA repair defects may have increased sensitivity to platinum-based chemotherapeutics.

 Given the uncertainty regarding optimal treatment selection and pending approval of current agents in trial, the National Comprehensive Cancer Network prostate cancer guideline panel recommends clinical trial enrollment for all men with prostate cancer and identified DNA repair gene mutations. In addition, somatic testing for specific gene variants may be undertaken.

For the most part, this approach is used in patients with advanced disease with the goal of identifying specific actionable targets. For example, mutations in HRR or MMR genes and identification of MSI-high versus MSI-low status may suggest certain treatments are more likely to be beneficial.

In addition to genetic testing of tumor tissue, assessing circulating tumor cells may offer important information. For example, testing of AR variant status can be performed using circulating tumor cells and may be predictive of disease.

Generally, genetic testing yields results that are unambiguous and will show that a gene mutation is present or absent. However, the reporting of the significance and association of that mutation relative to a disease state can be quite variable. Given that the coding sequence for a particular gene has been defined and the sequencing machines are fairly similar, what is considered “positive” or deleterious versus “negative” or favorable/no mutation relative to risk of disease is predicated on the number of patients tested.

As noted, a number of genes have been identified as associated with an increased susceptibility risk for prostate cancer. Multigene panels are becoming used more often, but the makeup of these panels is not uniform. A recent analysis looking at various commercially available multigene panels shows that the average number of genes tested is 12 (range, 4-16). 

 are included in all the panels, but 20% did not include 

The clinical experience and number of patients tested with 

 is more extensive compared with other genes. More and more mutations continue to be discovered, but the significance to the patient has yet to be determined until even further samples are processed. These discoveries, classified as variants of unknown significance (VUS), represent a gray area in which there is a change in the genetic sequence; however, it is still unknown whether this change is associated with a deleterious or favorable prognosis. Among women with breast cancer, detection of a VUS is more common than identification of known pathogenic variants.

 Although ongoing work seeks to better delineate the importance of these VUS, the involvement of a genetic counselor is key to helping patients navigate this uncertain situation.

Urologists will need to incorporate comprehensive genomic testing, just as we embraced PSA testing back in the 1990s. A recent survey conducted among 52 single-specialty independent urology community practices identified the following three issues related to incorporation and development of a comprehensive testing program

• medical/legal liability for unaddressed identified mutations

• reimbursement concerns and cost of testing

• complexity and time involved to enter a complete family history and pedigree into the electronic health record.

None of these considerations, however, is insurmountable if the practice has a commitment to enhance and deliver precision medicine for our patients with prostate cancer.

1. Siegel RL, Miller KD Jemal A. Cancer statistics, 2019. 

2. Scher HI, Solo K, Valant J, Todd MB, Mehra M. Prevalence of prostate cancer clinical states and mortality in the United States: estimates using a dynamic progression model. 

3. Rubin MA, Maher CA, Chinnaiyan AM. Common gene rearrangements in prostate cancer.

4. Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. 

5. Castro E, Romero-Laorden N, Del Pozo A, et al. PROREPAIR-B: a prospective cohort study of the impact of germline DNA repair mutations on the outcomes of patients with metastatic castration-resistant prostate cancer. 

6. Nicolosi P, Ledet E, Yang S, et al. Prevalence of germline variants in prostate cancer and implications for current genetic testing guidelines.

7. Robinson D, Van Allen EM, Wu YM, et al. Integrative clinical genomics of advanced prostate cancer. 

8. Wu YM, CieÅlik M, Lonigro RJ, et al. Inactivation of CDK12 delineates a distinct immunogenic class of advanced prostate cancer. 

9. Humeniuk MS, Gupta RT, Healy P, et al. Platinum sensitivity in metastatic prostate cancer: does histology matter? 

10. Aldubayan SH. Considerations of multigene test findings among men with prostate cancer–knowns and unknowns. 

11. van Marcke C, Collard A, Vikkula M, et al. Prevalence of pathogenic variants and variants of unknown significance in patients at high risk of breast cancer: a systematic review and meta-analysis of gene-panel data. 

12. Concepcion RS. Germline testing for prostate cancer: community urology perspective. 

Advances in genomic testing will help determine lines of therapy in men with mCSPC and mCRPC, according to Raoul S. Concepcion, MD.

Role and rationale for molecular testing in advanced prostate cancer

Bladder cancer is traditionally thought of as almost two distinct cancers, with nearly 80% of newly diagnosed cases being nonmuscle-invasive disease (NMIBC). The challenge of managing patients with NMIBC is predicting which patients are at risk for progression to muscle-invasive bladder cancer (MIBC), where treatment is much more aggressive and life altering, versus those that are at a much lower risk and potentially the surveillance can be altered with a concomitant reduction in costs.

For patients with higher risk NMIBC, the mainstay of therapy has historically been bacillus Calmette–GuÃ©rin (BCG). However, because of the ongoing BCG shortage in addition to the lack of effective alternative drug therapies for patients with BCG-unresponsive disease, a large unmet need exists for these patients and providers. Newer agents are addressing these challenges. 

discusses these therapies, their specific indications, how they are administered, dosing, and side effects.

Dr. Galsky is professor of medicine, director of genitourinary medical oncology, director of the Novel Therapeutics Unit, and co-director of the Center of Excellence for Bladder Cancer at The Tisch Cancer Institute and the Icahn School of Medicine at Mount Sinai, New York. He was interviewed by 

, chief clinical urologic officer, Integra Connect, West Palm Beach, FL, and clinical associate professor of urology, Vanderbilt University School of Medicine, Nashville, TN.

What are the current challenges associated with the treatment of NMIBC?

There are two major challenges. One is in patients who are treatment naive, and that challenge is that there's a shortage of the standard-of-care treatment for patients with high-risk nonmuscle-invasive disease, which is BCG. That creates some challenges in terms of clinical management, but it also creates challenges in terms of clinical trials in that if you don't have the standard of care as a control treatment, then it's difficult to run clinical trials that are randomized or with combination therapies, etc.

The second major challenge has existed for a bit longer, and that's how we optimally manage patients who have BCG-unresponsive carcinoma in situ, ie, patients who have not adequately responded to treatment with BCG. We know that the standard of care in that context is radical cystectomy, but that's a treatment many patients would like to avoid if possible. That's led to a long history of studies seeking to determine whether or not there are medical treatments that can be used to avoid cystectomy, ideally, or at the very least, delay it.

Please discuss developments that will address one or both of those challenges. What do you anticipate will be approved for the management of NMIBC over the next 12 months, especially in the BCG non-responsive patient?

Pembrolizumab (KEYTRUDA), the PD-1 inhibitor, has already been approved for the treatment of BCG-unresponsive disease. That approval was based on a single-arm study that involved two cohorts. We only have the results of one of those cohorts-patients with BCG-unresponsive disease who had carcinoma in situ with or without papillary disease-so that was the basis for the approval. Pembrolizumab is the first systemic treatment approved in this context.

The second cohort included patients with only papillary disease, either high-grade Ta disease or T1 disease, and we don't have the results from that cohort yet. That's potentially an important point that's often missed in clinical situations as medical oncologists like myself get some referrals for patients with nonmuscle-invasive disease who don't specifically meet the eligibility criteria that were the basis for the approval of pembrolizumab. 

Incidentally, another systemic therapy, atezolizumab, which is a PD-L1 inhibitor, was being studied in a similar context in SWOG-1605, and that trial closed prematurely. It failed to meet the threshold for which it was likely to be a successful trial. We don't fully understand the results of that study yet and the nuances of pembrolizumab versus atezolizumab in this setting.

There are also two intravesical treatments that are being reviewed by the FDA, and the expectation is that one or both of these drugs will likely become available as well. These agents include nadofaragene firadenovec (Instiladrin), which is an interferon-alpha expressing-adenovirus, and that has been studied in nonmuscle-invasive BCG-unresponsive disease and led to a 12-month complete response rate of 24%, which is encouraging in this context, particularly based on the route and frequency of administration.

A second intravesically administered drug is called Vicinium, which is a fusion protein consisting of an epithelial cell adhesion molecule (EpCAM) that is fused to a Pseudomonas exotoxin, essentially delivering this exotoxin to EpCAM-expressing cells. Vicinium has been studied in a single-arm study with a 12-month complete response rate of 17%.

The 12 month-complete response rates with pembrolizumab, nadofaragene, and Vicinium-even though these cohorts are not exactly the same and there are some nuances in terms of study eligibility-line up fairly well at between 17% and 24%.

How are these three therapies administered?

Pembrolizumab is administered intravenously every 3 weeks. In the clinical trial that led to its approval, it was administered for up to 2 years as long as there wasn't evidence of recurrence or progression. Nadofaragene is administered intravesically every 3 months for up to 4 years. Vicinium is administered intravesically one to two times a week for 12 weeks, and then every 2 weeks for 2 years.

Will the approvals be for high-grade TA, T1 disease, and carcinoma in situ?

As I mentioned, the approval for pembrolizumab was based on one of the two cohorts that were explored in that study, and that was a cohort of patients with carcinoma in situ with or without papillary disease (Ta or T1 disease). Results for Cohort B, which was in patients with papillary disease, are not available yet. So far, the approval of pembrolizumab is in patients with carcinoma in situ, and we'll have to see if that's extended based on the initial results.

In the nadofaragene and the Vicinium trials, if these therapies are indeed approved, it will be interesting to how restricted the label might be with regard to the type of NMIBC.

Will these agents be approved for primary therapy, given the current BCG shortage?

I don't suspect they'll be approved as primary therapy in the near term, even with the BCG shortage. I think the question, though, is will they be used in the absence of BCG? When there are drug shortages in other disease states, we see some extrapolations of data, so it wouldn't be a surprise to me if we start to see some of these drugs being used in that context if BCG can't be obtained.

In the longer term, whether or not these therapies have the potential to be compared to BCG in randomized studies and ultimately replace BCG remains to be seen. We know there are studies with immune checkpoint blockade in combination with BCG aimed at potentially finding a drug to replace maintenance BCG, which could certainly lighten the load in terms of the need to source BCG. Those studies are probably coming in the future, but I don't suspect the approvals will be for that use in the short term.

For the immunologic agents, will there be both induction and maintenance dosing?

There isn't induction and maintenance dosing per se, but there is long-term treatment, at least based on the initial study. With pembrolizumab, the treatment is administered for up to 2 years in the absence of recurrence or progression. The dosing, though, is the same, and the schedule is the same. Unlike with BCG, where the schedule changes with maintenance, pembrolizumab is administered potentially for a long term, but with the same dosing schedule. The optimal duration of immune checkpoint inhibitors, even in the metastatic setting, remains unclear.

How do you anticipate that medical oncologists, who have historically not managed nonmuscle-invasive bladder cancer patients, and urologists will use these newer agents?

That's going to be an evolving question, at least in part based on longer term follow-up data from these studies and, of course, the pending approvals of Vicinium and nadofaragene. The reason I say that is, if you look across the studies with those three agents-and again, it's somewhat dangerous to do that because they're not randomized and the eligibility doesn't exactly line up-the proportion of patients who have a complete response at 12 months is pretty similar.

Then you need to think about other factors to help make the decision about choice of treatment, which include the potential side effects of treatment, the mode of administration, the frequency of administration, and potentially the cost. One can develop a scorecard of those items for each of these individual therapies. If there's an intravesical treatment that works potentially just as well, spares systemic side effects, and is administered less frequently, then that may be a preferable treatment from the standpoint of patient and physician.

However, one also need to consider the long-term follow-up data from these trials. The goal of giving these treatments is really to avoid cystectomy ideally more so than delay cystectomy. If our goal is to avoid cystectomy, then we are looking for treatments that are potentially curative in at least a subset of patients. If there is a subset of patients who are cured with these treatments, rather than just experiencing a delay in recurrence or progression, then the value proposition of that treatment changes a bit. So if immune checkpoint blockade given for a fixed period of time, say 2 years, leads to eradication of cancer and durable remission in a subset of patients, that might balance against the inconvenience of intravenous administration and the risk for systemic side effects. So, treatment paradigms are in evolution based on all of these considerations.

What are the side effects of the three agents you discussed?

The side effect profile of pembrolizumab is pretty well defined based on its approval in metastatic cancers. Pembrolizumab and other immune checkpoint inhibitors are widely approved in various solid tumors and hematologic malignancies as well, so we have a pretty good understanding of the potential side effects, which don't seem to differ in the NMIBC patient population. Based on the KEYNOTE study that led to the approval of pembrolizumab, there was a 13% likelihood of having treatment-related moderate to severe (grade 3 to 5) side effects. Those side effects include the potential for inflammation of various parts of the body: colitis, pneumonitis, dermatitis, hepatitis, etc.

When those side effects occur, they often resolve with simply stopping the medication. Sometimes steroid medications are required to help resolve those side effects.

With nadofaragene and Vicinium, there are side effects similar to other local therapies. Grade 3 to 5 side effects in the trials of those drugs were in the 4% range. We do see a different side effect profile when treatments are administered into the bladder versus when they're administered systemically.

What is the role of chemoradiation in chemoradiation for high-grade T1 bladder cancer?

That is one topic that often gets left out of the conversation. We know that chemoradiation has a role for muscle-invasive bladder cancer. Its role in T1 high-grade disease, particularly post-BCG, is not entirely well defined.

There was a fairly large study looking at chemoradiation for BCG-naive, high-grade T1 disease that showed reasonable bladder-intact outcomes. That concept is being explored in an RTOG study in patients who have already received BCG. It is an option that we think about for T2 disease, but oftentimes we don't think about it for T1 disease, possibly because of the absence of data in this in the post-BCG setting.

What is the status of molecular markers for NMIBC?

The major molecular marker that's potentially relevant is a mutation in a gene called fibroblast growth factor receptor 3, or FGFR3. We know that FGFR3 is mutated in a large subset of low-grade, nonmuscle-invasive bladder cancers, but it's mutated in a smaller subset of high-grade cancers as well. Erdafitinib (BALVERSA) is an orally bioavailable, small-molecule inhibitors of this receptor that is now approved by the FDA for the treatment of metastatic bladder cancer.

Thus, a logical question is whether or not those treatments can be effective in patients who have FGFR3-mutated nonmuscle-invasive bladder cancer. Some pilot studies have suggested intriguing results, but there are large studies that have just been initiated with more definitive endpoints, trying to determine whether or not this could be the first "precision medicine-based" approach for nonmuscle-invasive disease.

Systemic and intravesical therapies are changing the landscape of BCG-unresponsive disease, according to Matthew Galsky, MD.

UCC April 2020

Robotics in GU oncology: Current status, future directions

Role and rationale for molecular testing in advanced prostate cancer

How new agents may address NMIBC treatment challenges