Conferences

SNMMI 2021: PSMA PET Drug Development: Clinical Trial Design and Statistical Considerations

(UroToday.com) The Society of Nuclear Medicine & Molecular Imaging (SNMMI) 2021 Annual Meeting included a session on FDA Radiopharmaceutical updates and a presentation by Drs. Shane Masters and Sue Jane Wang discussing clinical trial design and statistical considerations for PSMA PET drug development. Dr. Masters notes that “Guidances by the FDA” are the FDA’s current thinking on a topic and are not legally binding documents. Furthermore, a ‘Guidance for Industry’ includes both academic and commercial sponsors.

SNMMI 2021: Practical Applications and Clinical Utility of an 18F PSMA-Targeted PET Imaging Agent: Implications for Urology and Radiation Oncology

(UroToday.com) In a Satellite Symposium at the Society of Nuclear Medicine & Molecular Imaging (SNMMI) 2021 Annual Meeting, Dr. Phillip Koo, Dr. E. David Crawford and Dr. Steve E. Finkelstein discussed the practical applications and clinical utility of 18F-PSMA-targeted positron emission tomography (PET) imaging for urologists and radiation oncologists.

SNMMI 2021: Metastatic Disease Response and Patterns of Recurrence in Men with High-Risk Prostate Cancer After Neo-Adjuvant Chemohormonal Therapy and Radical Prostatectomy Utilizing PSMA-Targeted 18F-DCFPyL PET/CT

(UroToday.com) Advances in imaging have dramatically reshaped prostate cancer diagnosis, staging, and treatment. While multiparametric MRI (mpMRI) of the prostate has dramatically changed prostate cancer diagnosis, molecularly-targeted imaging has reshaped disease staging and detection of recurrent disease. Conventional imaging approaches using including computed tomography (CT) and bone scan have relatively limited sensitivity to detect disease recurrence following initial local therapy. A number of studies have demonstrated that prostate-specific membrane antigen (PSMA) targeting PET radiopharmaceuticals detect disease not identified based on conventional imaging, with greater accuracy, for initial staging and detection of biochemical recurrence. In a presentation in the Center for Therapy Excellence Young Investigator Award session at the Society of Nuclear Medicine & Molecular Imaging (SNMMI) 2021 Annual Meeting, Dr. Petra Lovrec discussed the potential for prostate-specific membrane antigen (PSMA)-based 18F-DCFPyL (PyL) PET imaging to predict metastatic disease response to therapy and to assess metastatic disease patterns of response and recurrence for patients receiving neoadjuvant chemohormonal therapy followed by prostatectomy for high-risk prostate cancer.

SNMMI 2021: 68Ga-PSMA PET/CT for Response Assessment and Outcome Prediction in Metastatic Prostate Cancer Undergoing Taxane-Based Chemotherapy

(UroToday.com) Advances in imaging have dramatically reshaped prostate cancer diagnosis, staging, and treatment. While multiparametric MRI (mpMRI) of the prostate has dramatically changed prostate cancer diagnosis, molecularly-targeted imaging has reshaped disease staging and detection of recurrent disease. Conventional imaging approaches using including computed tomography (CT) and bone scan have relatively limited sensitivity to detect disease recurrence following initial local therapy. A number of studies have demonstrated that prostate-specific membrane antigen (PSMA) targeting PET radiopharmaceuticals detect disease not identified based on conventional imaging, with greater accuracy, for initial staging and detection of biochemical recurrence. However, its role in response assessment has not been thoroughly investigated.

SNMMI 2021: Safety and Efficacy of Radioligand Therapy with 177lutetium-PSMA-617 Within 3 Months After 223Radium-Dichloride

(UroToday.com) Beginning with the introduction of docetaxel for metastatic castration resistant prostate cancer (mCRPC) in 2004, there has been a dramatic and rapid proliferation of systemic therapy options in advanced prostate cancer including a number of novel hormonal therapies (including abiraterone acetate and enzalutamide), second-line chemotherapy (cabazitaxel), bone-targeting agents (radium-223) and other targeted agents (including olaparib, rucaparib, and pembrolizumab), each of which has proven survival benefits. Radium-223 acts as an alpha-emitting calcium mimetic which targets bony metastatasis. Recently, theranostic treatment with prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy, including most notably 177lutetium-PSMA-617 as well as others, has demonstrated promising activity among pre-treated individuals with mCRPC. Given the similarity of radionuclide activity between 177lutetium-PSMA-617 and radium-223, in the Center for Therapy Excellence Young Investigator Award session at the Society of Nuclear Medicine & Molecular Imaging (SNMMI) 2021 Annual Meeting, Dr. Justus Baumgarten explored the feasibility of immediate onset of 177lutetium-PSMA-617 after radium-223.

ASCO 2021: Differences in the Pattern of and Response to Treatment: Not Just Race

(UroToday.com) In this educational session, Dr. Heath discussed the variability in prostate cancer treatments and outcomes based on geographic location and race.

Within localized disease, Dr. Heath highlighted data published in 2020 from the National Cancer Database, which includes over 214,000 men diagnosed with high-risk prostate cancer between 2004 and 2016. This disease is typically managed with either prostatectomy or radiotherapy. Black men are less likely to undergo prostatectomy from historical data, but this gap is narrowing with time. For patients treated with prostatectomy, Black men have a 20% higher mortality than white men, whereas Asian men have a 35% lower mortality than white men. From SEER data, there is a suggestion that in low-risk prostate cancer, Black men are more likely to die than white men, though it is important to note that information on causes of death is lacking in this cohort. With regards to radiotherapy, SEER data suggests that Black and Hispanic men are less likely to receive therapy. Black men have slightly higher rates of not completing radiotherapy, but when examining treatment strategies with lower numbers of total fractions (SBRT), no disparity in completion rates between Blacks and Whites has been noted.

Dr. Heath also noted that ethnicity is a complex construct. For example, cancer incidence rates differ between Hispanic patients (those from Spanish-speaking countries) and Latino patients (those from Latin American countries like Brazil). She showed a figure looking at incidence rates of different cancers with Hispanic males, illustrating that the rates vary based on country of origin.

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Place of residence (rural vs urban) also matters. Patients living in rural areas, even when controlling for urologist density, are less likely to receive treatment for prostate cancer. Patients in rural areas need as much supportive interventions as other patients, but data suggests the quality of life is lower for prostate cancer survivors living in rural areas. This may be due to delays in treatment resulting in more advanced disease, local cultural taboos about talking about the effects of treatment, or limited access to supportive care like mental health services. However, place of treatment (academic vs community center) research suggests that both academic and community centers have equal amounts of disparities in the treatment of minorities and uninsured patients with high-risk localized prostate cancer. This includes access to imaging studies with prostate-cancer-specific advanced imaging techniques.

Data from Switzerland suggests that patients with higher socioeconomic status have a lower risk of death than patients with low socioeconomic status. Patients with lower socioeconomic status also tended to be older at the age of diagnosis with more advanced disease/higher tumor grade.

Dr. Heath then focused on available surrounding how different racial groups respond to treatments for advanced prostate cancers. African American patients with minimally symptomatic castration-resistant prostate cancer treated with sipuleucel-T were found to have improved overall survival relative to Caucasian patients in the PROCEED registry (https://doi.org/10.1038/s41391-020-0213-7). In a meta-analysis of ten phase 3 trials of patients treated with docetaxel chemotherapy for metastatic castration-resistant prostate cancer (https:doi.org/10.1200/JCO.18.01279), researchers found equivalent median overall survival (21 months) for both Black and White men, though the pooled hazard ratio suggested a superior overall survival for Black men (HR 0.81, 95% CI 0.72-0.91). Patients treated within the Veterans Affairs system with radium-223 were found to have a decreased risk of mortality and numerically longer overall survival relative to non-Black patients (https://doi.org/ 10.1097/JU.0000000000000524). Comparisons by race for PSA responses with abiraterone acetate as front-line therapy for metastatic castration-resistant prostate cancer suggest superior median PSA progression-free survival for Black patients (16.6 months vs 11.5 months). Analysis of the 7-month PSA response rate for enzalutamide therapy as first-line treatment for metastatic castration-sensitive prostate cancer suggests equivalent rates in Black and White patients (93% vs 94%), but much lower rates for Black patients with bicalutamide (42% vs 86%). In total, these studies suggest that Black patients have equivalent or improved outcomes with therapies administered for advanced prostate cancer when administered especially in the monitored and supported setting of a clinical trial.

Finally, Dr. Heath talked about disparities in clinical trial accrual and data collection across different racial groups. She showed the following summary slide. Globally, disparities in enrollment in trial exist, with 96% of patients enrolled in the global phase 3 or 4 trials in prostate cancer identifying as White.

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Efforts are underway to improve data collection and greater inclusivity in prostate cancer. One example is the IRONMAN registry, a global effort to include all men with advanced prostate cancer to provide information on care. A multilevel intervention to increase the participation of African Americans in Prostate Cancer (PAACT) initiative is also underway to help enroll African American patients into trials.

Finally, Dr. Heath provided the following suggestion slide for what providers can do to be more mindful of disparities and attempt to address them.

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Presented by: Elisabeth I. Heath, MD, FACP, Hartmann Endowed Chair for Prostate Cancer Research and Professor of Oncology at the Karmanos Cancer Center, Detroit, MI

Written by: Alok Tewari, MD, Ph.D., Medical Oncologist at the Dana-Farber Cancer Institute, at the virtual 2021 American Society of Clinical Oncology Annual Meeting Congress (#ASCO21), June 4th-June 8th, 2021

ASCO 2021: Optimizing Urothelial Cancer Management From Organ-Confined to Metastatic Disease: A Multidisciplinary Approach – Urologic Oncologist Perspective

(UroToday.com) This session was a multidisciplinary case discussion focusing on multiple topics including (1) treatment of BCG unresponsive non-muscle invasive bladder cancer, (2) treatment of muscle-invasive urothelial carcinoma in cisplatin eligible and ineligible patients, (3) the implications of pathologic response to neoadjuvant chemotherapy, (4) the role of adjuvant therapy, (5) the management of metastatic urothelial carcinoma and the role of chemotherapy, immune therapies, FGFR inhibition, and antibody-drug conjugates, and finally (5) palliative therapy.

Case: 62F presents with gross hematuria and undergoes cystoscopy.

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Dr. Lee discussed the cystoscopy findings as a couple of areas of erythema that appear released. In this patient, she would be initially concerned for carcinoma in situ. In the pathology slide, we have labeled carcinoma in situ (CIS). This is an important diagnosis to make earlier because we think it is a precursor to invasive disease, and so I would be interested in talking with her about intravesicular therapy. We still look to intravesical BCG for our first-line treatment, roughly 2/3 of patients will respond initially, and about ½ of patients will have a long-term benefit. After induction BCG, we know that maintenance therapy reduces the risk of recurrence and disease progression. Most urologists follow the SWOG schedule for high-risk patients (such as patients with carcinoma in situ), which provides a course of induction BCG with six doses and then maintenance therapy at 3, 6, 12, 18, 24, 30, and 36 months post-induction so long as the patient tolerates therapy and has no recurrence.

Case continued: She is diagnosed with carcinoma in situ and receives intravesicular BCG for six treatments followed by maintenance therapy. After six months of maintenance therapy, her surveillance cystoscopy reveals recurrence carcinoma and situ and a new invasive T1 urothelial carcinoma.

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Dr. Lee commented that this appears to be a more concerning tumor based on size with neovascularity around the edges and erythema at the 6 o’clock position. Based on the appearance with some suggestion of papillation, she would worry about an invasive component, and so would suggest transurethral resection of the bladder tumor (TURBT), examination under anesthesia, and upper tract imaging. The degree of invasion seen on the pathology slide (more extensive, not focal) is concerning for an even higher risk of future prediction.

The first question posed was “What treatment option would you proceed with?”. (A) Intravesical chemotherapy, (B) Intravenous pembrolizumab, (C) Radical Cystectomy, or (D) Other.

Dr. Lee discussed that based on her early timing of relapse, if the patient has reasonable performance status, then she would be talking about radical cystectomy. Not everyone will agree with this and many will remain committed to bladder preservation at this point. If she does not agree to cystectomy then I think about second-line therapies including pembrolizumab or intravesical chemotherapy. More and more provocative data is emerging from studies looking at gemcitabine and docetaxel sequentially with intravesical chemotherapy, which in recent data is well-tolerated and showing 50% recurrence-free survival at two years. Though this is retrospective data, it is provocative and likely warrants a clinical trial.

I would pursue re-resection here if the patient does not opt for cystectomy to take a deeper resection.

The patient is not interested in radical cystectomy or intravenous pembrolizumab due to travel requirements. She is willing to receive intravesical chemotherapy with gemcitabine and docetaxel.

Dr. Lee commented that for a long time valrubicin was the only FDA-approved option for intravesical chemotherapy in BCG-unresponsive patients. Unfortunately, this was not durable, as less than 10% of patients were free of disease after two years. Also, for this patient who has travel concerns, it is possible to think of every 6-week infusion schedule for pembrolizumab. However, it is important to monitor these patients on pembrolizumab with labs, so in her practice, she typically throws in a telehealth visit. She also discussed the potential role of nadofaragene firadenovec, which is a non-replicating adenoviral vector that induced interferon alfa-2B destruction of tumors. It’s delivered every three months and not yet approved but appears promising. She also discussed the potential emerging role of oportuzumab monatox (single-chain monoclonal antibody fragment against EpCAM conjugated to a truncated form of Pseudomonas exotoxin that inhibits protein synthesis in target cells), and FGFR inhibitors in BCG-unresponsive disease.

After intravesical chemotherapy, surveillance cystoscopy performed 6 months later reveals invasive disease obscuring the bilateral ureteral orifices, resulting in kidney injury. CT imaging reveals bilateral hydronephrosis but no significant lymphadenopathy.

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Dr. Lee discussed that this bladder view, which appears to be in the operating room, is very concerning for recurrence which encompasses most of the visual field and appears more nodular than papillary. The presence of bilateral hydronephrosis and is suggestive of extravesicular disease and potentially vaginal invasion. An exam under anesthesia will be important to fully stage the patient. Given the likelihood that the disease is obstructing both ureteral orifices, it would likely be difficult to place internalized stents, so she would probably opt for percutaneous nephrostomy tubes in this patient to improve her renal function. It is important to remember that patients are never excited about external tubes and drains that they have to manage as it impacts their quality of life.

Bilateral percutaneous nephrostomy tubes are recommended, and the patient wants to start treatment as soon as possible. Her ECOG PS is 1 and she has no other major comorbidities. What options do you consider? (A) Radical cystectomy, (B) Split-dose cisplatin-combination chemotherapy followed by cystectomy, (C) carboplatin-combination chemotherapy followed by cystectomy, (D) pembrolizumab followed by cystectomy, (E) Bladder preservation with cisplatin-based chemoradiation, (F) Bladder preservation with 5FU based chemoradiation.

Dr. Lee discussed the promising data from RTOG 0712 exploring the role of trimodality therapy for bladder preservation. However, patients were not recruited to this trial if they had prognostic factors that suggest they might fail, and so it is important to consider what the most efficacious therapy might be in the context of whatever prognostic factors are present.

Although primary cystectomy is possible, we have level 1 evidence to show improved survival outcomes with neoadjuvant cisplatin-based chemotherapy as well as provocative early data showing reasonable pT0 rates in neoadjuvant pembrolizumab. Her preference would be to avoid primary cystectomy unless no neoadjuvant therapy can be administered.

With bilateral nephrostomy tubes, the creatinine clearance improves to 61 ml/min and becomes cisplatin eligible. She prefers surgery but would be willing to receive neoadjuvant chemotherapy if recommended. The patient undergoes accelerated MVAC and then radical cystectomy with an ileal conduit. Pathology reveals ypT2N0 disease.

The goal of neoadjuvant therapy, dating back to the SWOG-8710 trial, is pathologic complete response (pCR). Patients who had pCR had overall survival improvement, with 85% of patients surviving at 5 years, which was very impressive. We know survival outcomes for patients who do not achieve pCR are worse, and also retrospective data showing that patients with the residual muscle-invasive disease do worse than those with residual non-muscle invasive disease.

What course of action would you recommend next? (A) Adjuvant carboplatin with gemcitabine, (B) Adjuvant taxane-combination chemotherapy regimen, (C) Adjuvant checkpoint inhibitor, (D) Observation

The most effective context for adjuvant therapy appears to be in patients with an extravesical component of residual disease. With an organ-confined state after neoadjuvant chemotherapy and surgery, I might favor observation.

The patient undergoes observation. Six months later, surveillance CT imaging reveals the following image. Creatinine clearance is now 48 ml/min and ECOG performance status is 1. Would you perform PD-L1 IHC on archival tissue to aid in treatment decision-making?

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The remainder of the session involved input from medical oncology as the patient developed the systemic disease. The take-home points below were provided at the end.

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Presented by: Cheryl T. Lee, MD, Urologic Oncologist and Chair of the Department of Urology at the Ohio State University, Colombus, OH

Written by: Alok Tewari, MD, Ph.D., Medical Oncologist at the Dana-Farber Cancer Institute, at the virtual 2021 American Society of Clinical Oncology Annual Meeting Congress (#ASCO21), June 4th-June 8th, 2021

SNMMI 2021: Imaging and Clinical Factors Impacting PSA Response in Patients with Metastatic Castrate Resistant Prostate Cancer Undergoing Lu177-PSMA-617 Therapy

(UroToday.com) Beginning with the introduction of docetaxel for metastatic castration resistant prostate cancer (mCRPC) in 2004, there has been a dramatic and rapid proliferation of systemic therapy options in advanced prostate cancer including a number of novel hormonal therapies (including abiraterone acetate and enzalutamide), second-line chemotherapy (cabazitaxel), bone-targeting agents (radium-223) and other targeted agents (including olaparib, rucaparib, and pembrolizumab), each of which has proven survival benefits. Recently, theranostic treatment with prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy, including most notably 177lutetium-PSMA-617 as well as others, has demonstrated promising activity among pre-treated individuals with mCRPC. However, there is no consensus on criteria to determine which patients will benefit the most from these therapeutic approaches. To address this gap, in the Cancer Radiopharmaceutical Therapy session at the Society of Nuclear Medicine & Molecular Imaging (SNMMI) 2021 Annual Meeting, Dr. Sarah Boughdad presented data that aimed to assess characteristics that might affect PSA response in patients undergoing Lu-177-PSMA-617 therapy.

ASCO 2021: Optimizing Urothelial Cancer Management From Organ-Confined to Metastatic Disease: A Multidisciplinary Approach – Radiation Oncologist Perspective

(UroToday.com) This session was a multidisciplinary case discussion focusing on multiple topics including (1) treatment of BCG unresponsive non-muscle invasive bladder cancer, (2) treatment of muscle-invasive urothelial carcinoma in cisplatin eligible and ineligible patients, (3) the implications of pathologic response to neoadjuvant chemotherapy, (4) the role of adjuvant therapy, (5) the management of metastatic urothelial carcinoma and the role of chemotherapy, immune therapies, FGFR inhibition, and antibody-drug conjugates, and finally (5) palliative therapy.

Case: 62F presents with gross hematuria and undergoes cystoscopy.

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She is diagnosed with carcinoma in situ (CIS) and receives intravesicular BCG for six treatments followed by maintenance therapy. After six months of maintenance therapy, her surveillance cystoscopy reveals recurrence carcinoma and situ and a new invasive T1 urothelial carcinoma.

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Dr. Vapiwala then commented on the pathology from the TURBT, which reveals invasion of the muscularis mucosa of the lamina propria. Muscle invasion is defined as invasion of the muscularis propria, and so to accurately assess this there needs to be muscularis propria present in your resection/biopsy specimen. This is a high-grade disease due to the presence of dense nuclei and invasion of muscularis mucosa but not muscularis propria, so we would call this pathologic T1 high-grade disease.

The first question posed was “What treatment option would you proceed with?”. (A) Intravesical chemotherapy, (B) Intravenous pembrolizumab, (C) Radical Cystectomy, or (D) Other.

Expert consensus in this discussion was that radical cystectomy is the best option for long-term disease control.

The patient is not interested in radical cystectomy or intravenous pembrolizumab due to travel requirements. She is willing to receive intravesical chemotherapy with gemcitabine and docetaxel. After intravesical chemotherapy, surveillance cystoscopy performed 6 months later reveals invasive disease obscuring the bilateral ureteral orifices, resulting in kidney injury. CT imaging reveals bilateral hydronephrosis but no significant lymphadenopathy. Bilateral percutaneous nephrostomy tubes are recommended, and the patient wants to start treatment as soon as possible. Her ECOG PS is 1 and she has no other major comorbidities. What options do you consider? (A) Radical cystectomy, (B) Split-dose cisplatin-combination chemotherapy followed by cystectomy, (C) carboplatin-combination chemotherapy followed by cystectomy, (D) pembrolizumab followed by cystectomy, (E) Bladder preservation with cisplatin-based chemoradiation, (F) Bladder preservation with 5FU based chemoradiation.

Dr. Vapiwala discussed that weighing patient wishes and goals of care in each context is really important, especially because there is an interest in bladder preservation trimodality therapy. This refers to maximal transurethral resection of bladder tumor followed by radiation and concurrent radiosensitizing chemotherapy. This has historically been chosen for patients who are deemed unfit for radical cystectomy or who refuse. Many clinical trials exclude patients with specific conditions that are typically related to poor prognosis (tumor greater than 6 cm, hydronephrosis, etc) and so these would need to be incorporated into the counseling of every patient’s specific context. The importance of multi-disciplinary discussion cannot be overstated. We also have more promising initial trial data that other chemotherapies other than cisplatin can be used for concurrent chemoradiation along with more sophisticated radiotherapy techniques. For this patient, I would want to know how her kidney function trends, and what her motivations with treatment are, and whether she might be interested in bladder preservation understanding that salvage cystectomy may be possible down the line. This would involve chemoradiation and then seeing if there is a good response, and if not, proceeding with radical cystectomy.

With bilateral nephrostomy tubes, the creatinine clearance improves to 61 ml/min and becomes cisplatin eligible. She prefers surgery but would be willing to receive neoadjuvant chemotherapy is recommended. The patient undergoes neoadjuvant dd MVAC and then radical cystectomy with an ileal conduit. Pathology reveals ypT2N0 disease. What course of action would you recommend next? (A) Adjuvant carboplatin with gemcitabine, (B) Adjuvant taxane-combination chemotherapy regimen, (C) Adjuvant checkpoint inhibitor, (D) Observation

The largest data set regarding adjuvant radiation therapy is a National Cancer Database study published in 2018. This study suggested while there was no overall survival benefit with adjuvant radiation in all patients, patients with positive surgical margins did have an overall survival benefit. One risk stratification criteria for trying to avoid locoregional recurrence is the Penn risk stratification method, which incorporates pathological T stage, margin status, and the number of lymph nodes identified during surgery. With regards to margin status, the location of the positive margin appeared to be important, with the highest risk of locoregional recurrence associated with a positive margin at the external/internal iliac region. While there are definitely toxicity concerns, intensity-modulated radiotherapy with image guidance can drastically reduce the risk to adjacent organs such as the bowel. For this patient, if a margin was positive, I would discuss the implication of the margin location, assess her overall function, and see how she felt about it as well.

The patient undergoes observation. Six months later, surveillance CT imaging reveals the following image. Creatinine clearance is now 48 ml/min and ECOG performance status is 1. Would you perform PD-L1 IHC on archival tissue to aid in treatment decision-making?

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Much of the intervening discussion focused on medical oncology options for systemic therapy.

The patient responds to enfortumab vedotin for 9 months before developing increasing back pain. ECOG PS is now 3. After obtaining a spine MRI, what will be your next course of action? (A) Hospice, (B) Radiation therapy, (C) Surgical decompression, (D) Palliative chemotherapy and bisphosphonates.

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Emerging data suggest that SBRT is superior for providing pain relief compared to conventional therapy and may improve clinical outcomes beyond pain control. Dr. Vapiwala would favor aggressive palliation with pain medication as well as SBRT to the lesion causing pain.

The session ended with key take-home points, which are shown below.

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Presented by: Neha Vapiwala, MD, Radiation Oncologist at the University of Pennsylvania, Philadelphia, PA

Written by: Alok Tewari, MD, Ph.D., Medical Oncologist at the Dana-Farber Cancer Institute, at the virtual 2021 American Society of Clinical Oncology Annual Meeting Congress (#ASCO21), June 4th-June 8th, 2021

SNMMI 2021: The Phase 3 VISION Trial: Evaluating the Efficacy of 177-Lu-PSMA (LuPSMA) in the Treatment of Patients with PSMA-Positive mCRPC

(UroToday.com) There has been a dramatic and rapid proliferation of systemic therapy options in advanced prostate cancer since the introduction of docetaxel for metastatic castration resistant prostate cancer (mCRPC) in 2004. These newer treatments have included a number of novel hormonal therapies (including abiraterone acetate and enzalutamide), second-line chemotherapy (cabazitaxel), bone-targeting agents (radium-223), and other targeted agents (including olaparib, rucaparib, and pembrolizumab), each of which has proven survival benefits. However, none of these agents have proven to be curative and there is, as a result, an ongoing need to identify novel treatment approaches. One of the approaches gaining the most interest is molecularly-targeted radionuclide therapy, leveraging molecularly targeting of cancer cells using prostate-specific membrane antigen (PSMA)-directed radioligands.

ASCO 2021: Optimizing Urothelial Cancer Management From Organ-Confined to Metastatic Disease: A Multidisciplinary Approach – Medical Oncologist Perspective

(UroToday.com) This session was a multidisciplinary case discussion focusing on multiple topics including (1) treatment of BCG unresponsive non-muscle invasive bladder cancer, (2) treatment of muscle-invasive urothelial carcinoma in cisplatin eligible and ineligible patients, (3) the implications of pathologic response to neoadjuvant chemotherapy, (4) the role of adjuvant therapy, (5) the management of metastatic urothelial carcinoma and the role of chemotherapy, immune therapies, FGFR inhibition, and antibody-drug conjugates, and finally (5) palliative therapy.

Case: 62F presents with gross hematuria and undergoes cystoscopy.

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She is diagnosed with carcinoma in situ (CIS) and receives intravesicular BCG for six treatments followed by maintenance therapy. After six months of maintenance therapy, her surveillance cystoscopy reveals recurrence carcinoma and situ and a new invasive T1 urothelial carcinoma.

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Dr. Hahn discussed that this would be termed BCG-unresponsive non-muscle-invasive bladder cancer. The term BCG-unresponsive, which has evolved over time through workshops and FDA consultations, is defined as recurrence of carcinoma in situ within 12 months of adequate BCG, or in a patient without CIS, if they had high-grade papillary disease recurrence within six months of adequate BCG. Adequate BCG is defined by the 5+2 rule, meaning they needed to have received at least 5 of the 6 planned induction treatments, then at least 2 of 3 maintenance therapies. We do not typically recommend additional BCG treatments for BCG-unresponsive patients.

The first question posed was “What treatment option would you proceed with?”. (A) Intravesical chemotherapy, (B) Intravenous pembrolizumab, (C) Radical Cystectomy, or (D) Other.

Dr. Hahn discussed some of the data behind intravenous pembrolizumab if the patient is not interested in cystectomy. This is an FDA-approved therapy for BCG-unresponsive patients with a component of CIS. Though this particular patient would have been eligible for KEYNOTE-57, which established this treatment as standard of care, it is important to note that in that trial the majority of patients were flat CIS alone, and only 1/3 had an associated high-grade papillary component. Based on data with advanced disease, where 15-20% of patients have disease durable control, we expect some patients to get long-term disease control in the non-muscle invasive patient as well. There are no clear biomarkers such as PD-L1 status that help identify patients more likely to respond. It is important to understand more deeply how the patient thinks about cystectomy because for pT1 disease it is the therapy that gives them the best chance for long-term durable disease control.

The patient is not interested in radical cystectomy or intravenous pembrolizumab due to travel requirements. She is willing to receive intravesical chemotherapy with gemcitabine and docetaxel. After intravesical chemotherapy, surveillance cystoscopy performed 6 months later reveals invasive disease obscuring the bilateral ureteral orifices, resulting in kidney injury. CT imaging reveals bilateral hydronephrosis but no significant lymphadenopathy.

From a medical oncology perspective, relieving ureteral obstruction with bilateral nephrostomy tubes helps us understand quickly if the patient can recover enough renal function to receive cisplatin-based chemotherapy. Second, it helps avoid start/stops with cisplatin, because if the renal function is worsening on the therapy you don’t have to consider ureteral obstruction as a potential reason. However, we must also be sympathetic to the quality-of-life decrease associated with these external drains and managing them. I try to emphasize especially in the pre-operative setting, that the goal is to facilitate the best chance of cure and hopefully the tubes will be only in for 2-3 months.

Bilateral percutaneous nephrostomy tubes are recommended, and the patient wants to start treatment as soon as possible. Her ECOG PS is 1 and she has no other major comorbidities. What options do you consider? (A) Radical cystectomy, (B) Split-dose cisplatin-combination chemotherapy followed by cystectomy, (C) carboplatin-combination chemotherapy followed by cystectomy, (D) pembrolizumab followed by cystectomy, (E) Bladder preservation with cisplatin-based chemoradiation, (F) Bladder preservation with 5FU based chemoradiation.

Based on the patient’s kidney injury, she would be likely ineligible for cisplatin, and at 38 mL/min, split dose chemotherapy is also concerning. We now have published data from Matt Galsky in JCO that set some uniform definitions of cisplatin eligibility, including performance status (0 or 1) and creatinine clearance of around 60. Other factors are also important such as baseline neuropathy, ototoxicity, or heart failure. However, in a patient that could receive curative therapy, many practitioners would lower the creatinine clearance threshold for cisplatin eligibility. Many people are comfortable going down to 50 if using split-dose cisplatin regimens, and this can be pushed a little further if nephrostomy tubes are in place and we can do adequate hydration, but 38 is a bit too low. Carboplatin can certainly be given, but I am not as comfortable with this in a patient who is cystectomy eligible. The role of immunotherapy is interesting given data from PURE-01 (pembrolizumab single agent) and ABACUS (single-agent atezolizumab). Even with brief exposure of three cycles relative to three months with chemotherapy, there is a complete response rate of 20-30%, but this still lives really in the clinical trial realm given that we do not know the long-term implications of complete response to immunotherapy. Multiple trials are ongoing, such as KEYNOTE-905 looking at pembrolizumab versus enfortumab vedotin (anti-nectin4 antibody-drug conjugate) versus cystectomy in cisplatin-ineligible patients.

With bilateral nephrostomy tubes, the creatinine clearance improves to 61 ml/min and becomes cisplatin eligible. She prefers surgery but would be willing to receive neoadjuvant chemotherapy if recommended. Do you agree or disagree?

Dr. Hahn agreed with neoadjuvant chemotherapy, and as a general statement does not have a clear preference between regimens. Both dose-dense MVAC and cisplatin/gemcitabine are accepted regimens, and in retrospective studies, there was no difference in pathologic complete responses or overall survival. Furthermore, in SWOG-1314 (COXEN), there was no difference in pathologic complete response in a randomized phase 2 trial between these two regimens, with an approximate 30% complete response rate.

The patient undergoes neoadjuvant dd MVAC and then radical cystectomy with an ileal conduit. Pathology reveals ypT2N0 disease. What course of action would you recommend next? (A) Adjuvant carboplatin with gemcitabine, (B) Adjuvant taxane-combination chemotherapy regimen, (C) Adjuvant checkpoint inhibitor, (D) Observation

Current guidelines recommend observation as there are no prospective data proving an advantage for any adjuvant chemotherapy, just retrospective and potentially flawed data. There have been two trials that have read out in this context. The IMvigor010 study of 800 patients looking at the impact of adjuvant atezolizumab in high-risk patients. No disease-free survival benefit was seen with the atezo treated group, and there was no clear subgroup that benefitted from therapy. CheckMate-274 looking at a similar population of over 700 patients showed a significant disease-free survival advantage for adjuvant nivolumab (21 months with nivolumab versus 10.9 months with placebo), but no overall survival data is available yet. Finally, we have the AMBASSADOR trial of adjuvant pembrolizumab that has not read out yet. As of today, I am not offering adjuvant checkpoint inhibitor therapy, but based on regulatory agency approvals and further clinical trial data, this may change.

The patient undergoes observation. Six months later, surveillance CT imaging reveals the following image. Creatinine clearance is now 48 ml/min and ECOG performance status is 1. Would you perform PD-L1 IHC on archival tissue to aid in treatment decision-making?

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For a patient with visceral liver metastases, I am not reaching towards immunotherapy first, and so PD-L1 IHC would not impact my treatment choice. If the patient is frail and not enthusiastic about carboplatin-based chemotherapy, then PD-L1 testing is useful especially if the label indication for immunotherapy requires it. At this point, given the quick relapse, this could be considered second-line therapy. While the responses to immunotherapy are not as good in liver metastases, patients with low-volume liver disease burden will have a chance of durable long-term disease control with immunotherapy.

PD-L1 testing is performed with the 22C3 antibody, and the CPS score returns at < 1. What course of action would you take next? (A) Gemcitabine with cisplatin, (B) Gemcitabine with carboplatin, (C) pembrolizumab, (D) gemcitabine with carboplatin plus atezolizumab

This is a tough question because the patient has relapse so soon after cisplatin-based chemotherapy, so would still be considering pembrolizumab therapy given the chance of durable response. Patients with a CPS score of less than 1 do have responses to immunotherapy. This is not a thrilling choice, but Dr. Hahn would favor pembrolizumab here.

Agree or Disagree: If the patient relapsed after 15 months instead of 6 months after neoadjuvant chemotherapy, that would change my systemic treatment selection.

Dr. Hahn would think more favorably about giving chemotherapy in this context, especially with the CPS score of less than 1. The chance of durable response in this patient is not high, but the presence of liver metastases is concerning for impending rapid expansion of systemic disease and so chemotherapy gives a better shot at a response. Dr. Hahn does not think it would be wrong to give immunotherapy given the chance of durability. Given that it is 12 months post neoadjuvant chemotherapy, there is an FDA label for immunotherapy if PD-L1 expression is high. However, he would favor chemotherapy more.

Agree or Disagree: I would obtain next-generation sequencing of the tumor at this time

Yes, given that an FDA-approved therapy for certain FGFR alteration-positive urothelial cancers, Dr. Hahn would sequence the tumor.

Foundation Medicine sequencing reveals a microsatellite stable tumor without hypermutation. There is no FGFR alteration or other actionable genomic alteration. The patient has a response to pembrolizumab for one year before liver metastases begin to grow and new lung and bone metastases are found on restaging imaging. What therapy would you proceed with next? (A) Taxane chemotherapy, (B) enfortumab vedotin, (C) Erdafitinib, (D) Sacituzumab govitecan

Dr. Hahn would favor enfortumab vedotin for two reasons: (1) presence of liver metastases where other therapies like taxanes have response rates of 10% but enfortumab has response rates in the 30-40% range, and (2) enfortumab has an overall survival advantage demonstrated compared to additional non-platinum-based chemotherapy in the randomized phase 3 trials. Because there is no proven overall survival advantage yet with Sacituzumab, though a promising strategy, he would go with enfortumab first.

The patient responds to enfortumab vedotin for 9 months before developing increasing back pain. ECOG PS is now 3. After obtaining a spine MRI, what will be your next course of action? (A) Hospice, (B) Radiation therapy, (C) Surgical decompression, (D) Palliative chemotherapy and bisphosphonates

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The session ended with key take-home points, which are shown below.

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Presented by: Noah M. Hahn, MD, Medical Oncologist at the Johns Hopkins University School of Medicine, Baltimore, MD

Written by: Alok Tewari, MD, Ph.D., Medical Oncologist at the Dana-Farber Cancer Institute, at the virtual 2021 American Society of Clinical Oncology Annual Meeting Congress (#ASCO21), June 4th-June 8th, 2021

SNMMI 2021: Osseous Molecular Radiotherapy for Metastatic Castration Resistant Prostate Cancer (mCRPC)

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