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Emerging Therapeutic Options for Low-Grade Non-Invasive Bladder Cancer: Primary Chemoablation

Introduction


Bladder cancer remains the sixth most commonly diagnosed cancer in the United States, with an estimate of 82,290 incident cases in 2023.1 At diagnosis, approximately 75% of patients present with non-muscle invasive disease, with significant clinical heterogeneity observed within this disease group.2,3 Patients with initial low-grade Ta disease (i.e., confined to the mucosal lining) represent a unique patient cohort given their favorable long-term oncologic outcomes, given that they are more likely to recur than progress to life-threatening disease.4
Written by: Rashid K. Sayyid, MD, MSc University of Toronto Toronto, ON and Zachary Klaassen, MD, MSc Medical College of Georgia Augusta, Georgia, USA
References:
  1. American Cancer Society. Key Statistics for Bladder Cancer.
  2. Babjuk M, Burger M, Comperat EM, et al. European Association of Urology guidelines on non-muscle-invasive bladder cancer (TaT1 and carcinoma in situ)—2019 update. Eur Urol 2019; 76(5):639-57.
  3. Monteiro LL, Witjes JA, Agarwal PK, et al. ICUD-SIU International Consultation on Bladder Cancer 2017: management of non-muscle invasive bladder cancer. World J Urol 2019; 37(1):51-60.
  4. Hernandez V, Llorente C, de la Pena E, et al. Long-term oncological outcomes of an active surveillance program in recurrent low grade Ta bladder cancer. Urol Oncol 2016; 34(4):165.e19-23.
  5. Mossanen M, Gore JL. The Burden of Bladder Cancer Care – Direct and Indirect Costs. Curr Opin Urol 2014; 24(5):487-91.
  6. Zhou Z, Zhao S, Lu Y, et al. Meta-analysis of efficacy and safety of continuous saline bladder irrigation compared with intravesical chemotherapy after transurethral resection of bladder tumors. World J Urol, 2019; 37(6):1075.
  7. Sylvester RJ, et al. Systematic Review and Individual Patient Data Meta-analysis of Randomized Trials Comparing a Single Immediate Instillation of Chemotherapy After Transurethral Resection with Transurethral Resection Alone in Patients with Stage pTa-pT1 Urothelial Carcinoma of the Bladder: Which Patients Benefit from the Instillation? Eur Urol 2016; 69(2): 231-44.
  8. Perlis N, Zlotta AR, Beyene J, et al. Immediate post-transurethral resection of bladder tumor intravesical chemotherapy prevents non-muscle-invasive bladder cancer recurrences: an updated meta-analysis on 2548 patients and quality-of-evidence review. Eur Urol 2013; 64(3):421-30.
  9. Messing EM, Tangen CM, Lerner SP, et al. Effect of Intravesical Instillation of Gemcitabine vs Saline Immediately Following Resection of Suspected Low-Grade Non-Muscle-Invasive Bladder Cancer on Tumor Recurrence: SWOG S0337 Randomized Clinical Trial. JAMA 2018; 319(18):1880-8.
  10. Arends TJH, Nativ O, Maffezzini M, et al. Results of a Randomised Controlled Trial Comparing Intravesical Chemohyperthermia with Mitomycin C Versus Bacillus Calmette-Guérin for Adjuvant Treatment of Patients with Intermediate- and High-risk Non-Muscle-invasive Bladder Cancer. Eur Urol 2016; 69(6):1046-52.
  11. Arends TJH, van der Heijdem AG, Witjes JA. Combined chemohyperthermia: 10-year single center experience in 160 patients with nonmuscle invasive bladder cancer. J Urol 2014; 192(3):708-13.
  12. Shelley MD, Kynaston H, Court J, et al. A systematic review of intravesical bacillus Calmette-Guérin plus transurethral resection vs transurethral resection alone in Ta and T1 bladder cancer. BJU Int 2001; 88(3):209-16.
  13. Han RF, Pan JG. Can intravesical bacillus Calmette-Guérin reduce recurrence in patients with superficial bladder cancer? A meta-analysis of randomized trials. Urology 2006; 67(6):1216-23.
  14. Shelley MD, Wilt TJ, Court J, et al. Intravesical bacillus Calmette-Guérin is superior to mitomycin C in reducing tumour recurrence in high-risk superficial bladder cancer: a meta-analysis of randomized trials. BJU Int 2004; 93(4):485-90.
  15. Bohle A, Jocham D, Bock PR. Intravesical bacillus Calmette-Guerin versus mitomycin C for superficial bladder cancer: a formal meta-analysis of comparative studies on recurrence and toxicity. J Urol 2003; 169(1):90-5.
  16. Popert RJ, Goodall J, Coptcoat MJ, et al. Superficial bladder cancer: the response of a marker tumour to a single intravesical instillation of epirubicin. Br J Urol 1994; 74(2):195-9.
  17. Mostafid AH, Porta N, Cresswell J, et al. CALIBER: a phase II randomized feasibility trial of chemoablation with mitomycin‐C vs surgical management in low‐risk non‐muscle‐invasive bladder cancer. BJU Int 2020; 125(6):817-26.
  18. Lindgren MS, Bue P, Azawi N, et al. The DaBlaCa-13 Study: Short-term, Intensive Chemoresection Versus Standard Adjuvant Intravesical Instillations in Non-muscle-invasive Bladder Cancer-A Randomised Controlled Trial. Eur Urol 2020; 78(6):856-62.
  19. Kleinmann N, Matin SF, Pierorazio PM, et al. Primary chemoablation of low-grade upper tract urothelial carcinoma using UGN-101, a mitomycin-containing reverse thermal gel (OLYMPUS): an open-label, single-arm, phase 3 trial. Lancet Oncol 2020; 21(6):776-85.
  20. FDA approves mitomycin for low-grade upper tract urothelial cancer.
  21. Chevli KK, Shore ND, Trainer A, et al. Primary Chemoablation of Low-Grade Intermediate-Risk Nonmuscle-Invasive Bladder Cancer Using UGN-102, a Mitomycin-Containing Reverse Thermal Gel (Optima II): A Phase 2b, Open-Label, Single-Arm Trial. J Urol 2022; 207(1):61-9.
  22. Prasad SM, Huang WC, Shore ND, et al. Treatment of Low-grade Intermediate-risk Nonmuscle-invasive Bladder Cancer With UGN-102 ± Transurethral Resection of Bladder Tumor Compared to Transurethral Resection of Bladder Tumor Monotherapy: A Randomized, Controlled, Phase 3 Trial (ATLAS). J Urol 2023; 101097JU0000000000003645.

New Cancer Bundle from CMS: the Enhancing Oncology Model

The Centers for Medicare and Medicaid Services have maintained a focus on transitioning the American healthcare system from a fee-for-service payment model to a value-based payment model. Medicare Access and CHIP Reauthorization Act of 2015 (MACRA) reformed the Medicare payment system and created two new pathways to move towards value.

The Treatment Landscape of Metastatic Urothelial Carcinoma: Second-Line Systemic Therapy

Introduction


For patients with metastatic urothelial carcinoma, first line therapy for cisplatin eligible patients remains platinum-based chemotherapy1 (followed by maintenance avelumab2), whereas those that are cisplatin ineligible may receive gemcitabine + carboplatin3 (followed by maintenance avelumab2), pembrolizumab,4 or pembrolizumab + enfortumab vedotin.5 Unfortunately, ~50% of patients will eventually have disease progression following first line therapy, which has historically been associated with a dismal prognosis.
Written by: Zachary Klaassen, MD, MSc Associate Professor of Urology Urologic Oncologist Medical College of Georgia, Georgia Cancer Center Augusta, GA and Rashid Sayyid, MD, MSc Urologic Oncology Fellow University of Toronto Toronto, Ontario, Canada
References:
  1. von der Maase H, Hansen SW, Roberts JT, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000;18: 3068-3077.
  2. Powles T, Park SH, Voog E, et al. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2020;383: 1218-1230.
  3. De Santis M, Bellmunt J, Mead G, et al. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. J Clin Oncol. 2012;30: 191-199.
  4. Powles T, Csoszi T, Ozguroglu M, et al. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22: 931-945.
  5. Hoimes CJ, Flaig TW, Milowsky MI, et al. Enfortumab Vedotin Plus Pembrolizumab in Previously Untreated Advanced Urothelial Cancer. J Clin Oncol. 2023;41: 22-31.
  6. Vaughn DJ, Broome CM, Hussain M, Gutheil JC, Markowitz AB. Phase II trial of weekly paclitaxel in patients with previously treated advanced urothelial cancer. J Clin Oncol. 2002;20: 937-940.
  7. Galsky MD, Mironov S, Iasonos A, Scattergood J, Boyle MG, Bajorin DF. Phase II trial of pemetrexed as second-line therapy in patients with metastatic urothelial carcinoma. Invest New Drugs. 2007;25: 265-270.
  8. McCaffrey JA, Hilton S, Mazumdar M, et al. Phase II trial of docetaxel in patients with advanced or metastatic transitional-cell carcinoma. J Clin Oncol. 1997;15: 1853-1857.
  9. Bellmunt J, Theodore C, Demkov T, et al. Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinum-containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract. J Clin Oncol. 2009;27: 4454-4461.
  10. Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med. 2017;376: 1015-1026.
  11. Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017;18: 312-322.
  12. Apolo AB, Infante JR, Balmanoukian A, et al. Avelumab, an Anti-Programmed Death-Ligand 1 Antibody, In Patients With Refractory Metastatic Urothelial Carcinoma: Results From a Multicenter, Phase Ib Study. J Clin Oncol. 2017;35: 2117-2124.
  13. Loriot Y, Necchi A, Park SH, et al. Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2019;381: 338-348.
  14. Knowles MA, Hurst CD. Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity. Nat Rev Cancer. 2015;15: 25-41.
  15. Sideris S, Aoun F, Zanaty M, et al. Efficacy of weekly paclitaxel treatment as a single agent chemotherapy following first-line cisplatin treatment in urothelial bladder cancer. Mol Clin Oncol. 2016;4: 1063-1067.
  16. Sternberg CN, de Mulder PH, Schornagel JH, et al. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol no. 30924. J Clin Oncol. 2001;19: 2638-2646.
  17. Yu EY, Petrylak DP, O'Donnell PH, et al. Enfortumab vedotin after PD-1 or PD-L1 inhibitors in cisplatin-ineligible patients with advanced urothelial carcinoma (EV‑201): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2021;22: 872-882.

National Cancer Drug Shortages: Policy Response and Potential Solutions

Although generic prescription drug shortages have been an ongoing problem over the past decade, the recent few months have brought about a severe chemotherapy shortage affecting many Americans with cancer. We explore the history and causes of this drug shortage in our last post.

BCG-unresponsive Non-Muscle Invasive Bladder Cancer: Immune Checkpoint Inhibitors

Introduction


Intravesical Bacillus Calmette-Guerin (BCG) currently remains the standard-of-care, guideline recommended treatment of choice in the adjuvant setting for intermediate- and high-risk non-muscle invasive bladder cancer (NMIBC) due to its ability to reduce the risk of disease recurrence and, more importantly, disease progression.1-3 However, despite adequate BCG treatment, defined as receipt of at least five doses of the initial six-dose induction course and at least 2/3 maintenance doses or at least 2/6 doses of the second induction course, up to 50% of such patients will develop a BCG-refractory, relapsing, or failure state.4 Currently, radical cystectomy remains the gold standard approach in this setting.1 However, many patients are either unfit or refuse cystectomy. As such, bladder-sparing approaches in this setting are of utmost importance.
Written by: Rashid K. Sayyid, MD, MSc University of Toronto Toronto, ON and Zachary Klaassen, MD, MSc Medical College of Georgia Augusta, Georgia, USA
References:
  1. EAU Guidelines: Non-muscle-invasive Bladder Cancer.
  2. Sylvester RJ, Brausi MA, Kirkels WJ, et al. Long-term efficacy results of EORTC genito-urinary group randomized phase 3 study 30911 comparing intravesical instillations of epirubicin, bacillus Calmette-Guerin, and bacillus Calmette-Guerin plus isoniazid in patients with intermediate- and high-risk stage Ta T1 urothelial carcinoma of the bladder. Eur Urol. 2010;57(5):766-73.
  3. Schmidt S, Kunath F, Coles B, et al. Intravesical Bacillus Calmette-Guérin versus mitomycin C for Ta and T1 bladder cancer. Cochrane Database Syst Review. 2020;1(1):CD011935.
  4. Babjuk M, Burger M, Comperat EM, et al. European Association of Urology Guidelines on non-muscle-invasive bladder cancer (TaT1 and carcinoma in situ) - 2019 Update. Eur Urol. 2019;76(5):639–57.
  5. Steinberg R, Bahnson R, Brosman S, et al. Efficacy and Safety of Valrubicin for the Treatment of Bacillus Calmette-Guerin Refractory Carcinoma in Situ of the Bladder. J Urol. 200;163(3):761-7.
  6. Bacillus Calmette-Guérin-unresponsive nonmuscle invasive bladder cancer: developing drugs and biologics for treatment guidance for industry. 2018.
  7. FDA approves pembrolizumab for BCG-unresponsive, high-risk non-muscle invasive bladder cancer.
  8. FDA D.I.S.C.O. Burst Edition: FDA approval of Adstiladrin (nadofaragene firadenovec-vncg) for patients with high-risk Bacillus Calmette-Guérin unresponsive non-muscle invasive bladder cancer with carcinoma in situ with or without papillary tumors.
  9. Kates M, Matoso A, Choi W, et al. Adaptive Immune Resistance to Intravesical BCG in Non–Muscle Invasive Bladder Cancer: Implications for Prospective BCG-Unresponsive Trials. Clin Cancer Res. 2020;26(4):882-91.
  10. Balar AV, Kamat AM, Kulkarni GS, et al. Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study. Lancet Oncol. 2021;22(7):919-30.
  11. Necchi A, Roumiguié M, Esen AA, et al. Pembrolizumab (pembro) monotherapy for patients (pts) with high-risk non–muscle-invasive bladder cancer (HR NMIBC) unresponsive to bacillus Calmette–Guérin (BCG): Results from cohort B of the phase 2 KEYNOTE-057 trial. J Clin Oncol. 2023;41(Supp 6):LBA442.
  12. Alanee S, Sana S, El-Zawahry A, et al. Phase I trial of intravesical Bacillus Calmette-Guérin combined with intravenous pembrolizumab in recurrent or persistent high-grade non-muscle-invasive bladder cancer after previous Bacillus Calmette-Guérin treatment. World J Urol. 2021;39(10):3807-13.
  13. Meghani K, Cooley LF, Choy B, et al. First-in-human Intravesical Delivery of Pembrolizumab Identifies Immune Activation in Bladder Cancer Unresponsive to Bacillus Calmette-Guérin. Eur Urol. 2022;82(6):602-10.
  14. Li R, Sexton WJ, Dhillon J, et al. A Phase 2 Study of Durvalumab for Bacillus Calmette-Guerin (BCG) Unresponsive Urothelial Carcinoma In Situ of the Bladder. Clin Cancer Res. 2023.
  15. Kowalski M, Guindon J, Brazas L, et al. A phase II study of oportuzumab monatox: an immunotoxin therapy for patients with noninvasive urothelial carcinoma in situ previously treated with bacillus Calmette-Guérin. J Urol. 2012;188(5):1712-8.
  16. Gurram S, Bellfield S, Dolan R, et al. PD09-04 Interim analysis of a phase I single-arm study of the combination of durvalumab (Medi4736) and vicinium (Oportuzumab Monatox, Vb4-845) in subjects with high-grade non-muscle-invasive bladder cancer previously treated with Bacillus Calmette-Guerin (Bcg). J Urol. 2021;206(Suppl 3):e120.
  17. Black PC, Tangen C, Singh P, et al. Phase II trial of atezolizumab in BCG-unresponsive non-muscle invasive bladder cancer: SWOG S1605 (NCT #02844816). J Clin Oncol;2020(Suppl):5022.
  18. Shore ND, Powles T, Bedke J, et al. A phase 3 study of the subcutaneous programmed cell death protein 1 inhibitor sasanlimab as single agent for patients with bacillus Calmette-Guérin, unresponsive high-risk, non-muscle invasive bladder cancer: CREST Study Cohort B. J Clin Oncol. 2022;40(Suppl 16):40.
  19. Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma. N Engl J Med. 2021;384:2102-14.
  20. Inman BA, Sebo TJ, Frigola X, et al. PD-L1 (B7-H1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata: associations with localized stage progression. Cancer. 2007;109(8):1499-505.
  21. Hudolin T, Mengus C, Coulot J, et al. Expression of Indoleamine 2,3-Dioxygenase Gene is a feature of poorly differentiated non-muscle-invasive urothelial cell bladder carcinomas. Anticancer Res. 2017;37(3):1375-80.
  22. Tabernero, et al. BMS-986205, an indoleamine 2,3-dioxygenase 1 inhibitor (IDO1i), in combination with nivolumab (NIVO): Updated safety across all tumor cohorts and efficacy in pts with advanced bladder cancer (advBC). J Clin Oncol. 2018;36(Suppl 15):4512.

National Cancer Drug Shortages: History and Current Status

Over the past decade, the United States has been facing ongoing issues regarding the supply and demand of generic prescription drugs. In general, generic drugs make up approximately 90% of prescriptions filled by American consumers. Given that these drugs are non-branded and have expired patients, they are manufactured at a lower cost.

BCG-Unresponsive Non-Muscle Invasive Bladder Cancer: Review of Intravesical Chemotherapy and Photodynamic Therapy

Introduction

Intravesical Bacillus Calmette-Guerin (BCG) remains the current standard-of-care, guideline-recommended treatment of choice in the adjuvant setting for intermediate- and high-risk non-muscle invasive bladder cancer (NMIBC) due to its ability to reduce the risk of disease recurrence and, more importantly, disease progression.1-3 Despite adequate BCG treatment up to 50% of patients will develop a BCG-refractory, relapsing, or failure state.4

Over the last several years, there has been a plethora of data in the BCG unresponsive disease space, leading to FDA approvals for pembrolizumab in January 2020 and nadofaragene firadenovec in December 2022.6 Many of these novel immune-based treatments overcome some of the limitations of older agents in this setting,7 particularly those related to short durations of exposure limiting their efficacy.8 This same concept of extending the intravesical exposure time has recently been extrapolated to the intravesical chemotherapeutic treatment landscape, where we have witnessed the emergence of novel agents with prolonged mechanisms of action and alternate methods of administration. In this Center of Excellence article, we will discuss the currently available evidence and ongoing studies for intravesical chemotherapeutic agents and photodynamic therapy in the BCG unresponsive NMIBC disease space.


Gemcitabine + Docetaxel

In 2020, the results of a multicenter, retrospective analysis evaluating sequential gemcitabine plus docetaxel in patients with recurrent NMIBC and a history of intravesical BCG treatment were reported. In this study, all patients received intravesical gemcitabine (1 gm/50 ml sterile water or saline) for 60 to 90 minutes, after which it was drained and intravesical docetaxel (37/5 mg/50 ml saline) was instilled and held for 1-2 hours. To minimize side effects secondary to the irritative effects of gemcitabine (pH 2.5), 1,300 mg of oral sodium bicarbonate was given the evening before and the morning of each instillation to alkalinize the urine. The induction regimen was given once weekly for 6 weeks, followed by monthly maintenance for up to 24 months in the majority of the participating institutions. Surveillance was performed in accordance with institutional/national guidelines.

This analysis included 276 patients with a median age of 73 years. The median number of prior BCG courses was 2 (range: 1 to 8), with 38% of patients meeting the BCG unresponsive disease definition. From an efficacy standpoint, the 1- and 2-year recurrence-free survival rates were 60% and 46%, respectively, with similar recurrence rates observed for patients with CIS versus papillary-only disease. The high-grade recurrence-free survival rates in the overall cohort at 1 and 2 years were 65% and 52%, respectively:

figure-1-intravesical-chemo.jpg

Among patients with BCG unresponsive disease, the 2-year high-grade recurrence-free survival rates were 50% and 58% for CIS and papillary disease-alone cases, respectively:

figure-2-intravesical-chemo.jpg

Overall, 43/276 patients (15.6%) underwent a radical cystectomy, at a median follow-up of 11.3 months, and 11 patients (4%) had evidence of progression to muscle invasive disease. The most common side effects were frequency/urgency and dysuria, with 41% of patients reporting symptoms during treatment, but only 9.3% having symptoms that impacted the treatment schedule. There were no reported treatment-related deaths.9

Long-term follow-up of a subset of this cohort from the University of Iowa was recently published in 2023. This analysis included 97 patients (35% BCG unresponsive), with a median follow-up of 49 months. The 3-month complete response rate was 74%, with a median duration of response of 25 months. The high-grade recurrence-free survival rates were:

  • 1 year: 60%
  • 2 years: 50%
  • 5 years: 30%
There were no significant differences in these rates between the overall and BCG unresponsive patients. During follow-up, 20 patients (20.6%) underwent a cystectomy and 15 patients (15.5%) experienced disease progression. The 5-year progression-free, cystectomy-free, cancer-specific, and overall survival rates were 82%, 75%, 91%, and 64%, respectively.10


Device-assisted Administration of Intravesical Chemotherapy

TAR-200

TAR-200/gemcitabine (JNJ-17000139) is a novel drug delivery system that allows for the sustained local release of gemcitabine intravesically, relying on an osmotic system as illustrated below:

figure-3-intravesical-chemo.jpg

Evaluation of urine and plasma gemcitabine concentrations over a 7-day period demonstrates the ability of TAR-200 to provide sustained, local delivery of gemcitabine while limiting systemic toxicity. As demonstrated in the figure below, intravesical instillation of gemcitabine (green curve) is associated with a sharp increase/decrease in the gemcitabine urine concentration, which is non-sustained beyond day 1. Conversely, we see an increase in the urinary gemcitabine concentration between days 1 and 3 with TAR-200 (blue curve), followed by a gradual decline with measurable levels detected until at least day 7. Importantly, no gemcitabine is detected in the plasma of patients receiving TAR-200.

figure-4-intravesical-chemo.jpg

SunRISe-1 is a randomized trial of BCG-unresponsive, high-risk NMIBC patients with CIS +/- papillary disease, who did not receive a radical cystectomy. Patients underwent stratified randomization (by presence or absence of concomitant papillary disease) in a 2:1:1 fashion to either:

  • Cohort 1: TAR-200 + cetrelimab (PD-1 inhibitor)
  • Cohort 2: TAR-200 alone (target sample size 50, currently enrolled: 23)
  • Cohort 3: Cetrelimab alone (target sample size 50, currently enrolled: 24)
Patients received TAR-200 every 3 weeks for the first 24 weeks, followed by every 12 weeks through week 96. Patients in the cetrelimab group received the drug through week 78. The primary endpoint was overall complete response. At AUA 2023, Dr. Sia Daneshmand presented the first results from the monotherapy arms of TAR-200 and cetrelimab alone groups of SunRISe-1 from a planned futility analysis (n=47 patients).

The median patient age was 70 – 72 years, pure CIS was present in 70% and 65% of patients in the TAR-200 and cetrelimab groups, respectively, and the median total doses of prior BCG were 12 in each arm. From an efficacy standpoint, 73% of patients in the TAR-200 arm achieved a complete response (median duration of response not yet reached), defined based on the results of cystoscopy, centrally assessed urine cytology, and mandated biopsy at weeks 24 and 48. The CR rate in the cetrelimab arm was 38%.

figure-5-intravesical-chemo.jpg

Overall, most adverse events in the TAR-200 group were grade ≤2, with those reported in the cetrelimab group similar to that expected and observed with other PD-1 agents. 9% and 4% of patients discontinued TAR-200 and cetrelimab due to treatment-related adverse events. In each arm, 1 patient had treatment-related serious adverse events and 2 patients had treatment-related grade ≥3 adverse events. No deaths were observed in the study.11

figure-6-intravesical-chemo.jpg

Given these promising findings from the TAR-200 monotherapy arm, Janssen announced that they will be suspending further enrollment to the TAR-200 + cetrelimab arm.


Radiofrequency-induced Thermochemotherapy

In 2009, the results of a multi-institutional analysis of 51 patients from 15 European centers receiving mitomycin combined with intravesical hyperthermia in patients with mainly BCG-failing CIS (35/51) were published. Patients received mitomycin via the Synergo® system SB-TS 101, which uses an intravesical microwave applicator to deliver hyperthermia to the bladder wall via direct irradiation, weekly for 6–8 weeks, followed by 4–6 sessions every 6–8 weeks. Of 49 evaluable patients, there was evidence of a complete CIS response (negative biopsy and cytology) at 3 months in 45 patients (92%). Patients had similar outcomes irrespective of whether they met the BCG failure definition or not. Among the 45 responders, 49% had a recurrence at a median follow-up of 22 months. The most common adverse events were bladder spasms (13.1%), pain (12.7%), and dysuria (6.2%), and were generally mild in severity.12

A follow-up analysis of 150 patients who received ≥6 radiofrequency mitomycin instillations (induction and maintenance) was reported in 2018. All included patients had either pathology or cystoscopy plus cytology available at 6 months of follow-up. Of these 150 patients, 50 (33.3%) had BCG-unresponsive disease, with a 6-months complete response rate of 36% in this subgroup. The two-year recurrence-free survival rate was 82.6%, with a three-year cystectomy-free rate of 71.4%. Treatment discontinuation due to adverse events occurred in 13.4% of patients receiving induction treatment and 17.8% of those receiving maintenance instillations.13


Hyperthermic Intravesical Chemotherapy

In 2018, de Joeng et al. reported the results of hyperthermic intravesical chemotherapy (HIVEC) in 52 patients with BCG unresponsive NMIBC. Patients received intravesical instillations of mitomycin (80 mg in 50 mL of distilled water) that were extravesically heated up to 41-43°C and recirculated during 60 minutes at 200 m/min at stable pressure. All instillations were conducted with the Combat BRS system V2.0. The 3-months complete response rate was 75%. By 12 months follow-up, 47% of patients had remained disease-free. The overall median disease-free survival was 17.7 months and was significantly longer in those with papillary disease at 28.8 months versus 17.7 months in those with CIS. Patients in the ‘very high risk’ BCG unresponsive group had the shortest disease-free survival duration at 12.1 months. Any adverse event was reported in 69% of patients, with almost all grade 1-2 in severity, most common of which was urinary frequency/urgency (35%), urinary tract pain (15%), and bladder spasms (7%).14

figure-7-intravesical-chemo.jpg

In 2022, results of the multi-institutional Hyperthermic Chemotherapy registry (HIVEC-E) were published. These included a total of 1,028 patients, with 172 (21%) and 74 (9%) having disease classified as BCG unresponsive and failure, respectively. The 12- and 24-months recurrence-free survival rates for the BCG unresponsive cohort were 78.1% and 57.4%, respectively. Among patients in the BCG unresponsive cohort, the 24-months recurrence-free survival rates were superior for those papillary only disease (64.5% versus 43.6% for those with CIS). Minor and severe adverse events occurred in 26% and 2% of patients, respectively.15


Photodynamic Therapy

TLD-1433 is a novel ruthenium-based photosensitizer that selectively binds to bladder cancer cells. When activated by a 520 nm intravesical laser (TLC-3200) under general anesthesia (90 J/cm2 of laser light), it generates cytotoxic singlet oxygen and radical oxygen species, leading to cell death. PDT is also known to induce an antitumor cascade of immune signaling.16,17

figure-8-intravesical-chemo.jpg

At ASCO GU 2023, Dr. Girish Kulkarni presented the interim results of a phase II trial evaluating this intravesical photo dynamic therapy in patients with BCG unresponsive CIS. At the time of presentation, the trial had enrolled 52 patients (70% pure CIS, 20% CIS + HG T1, 10% CIS + Ta). This was a heavily pre-treated cohort, with 21% having >19 prior BCG instillations. A complete response, defined by a negative cystoscopy and cytology, was observed in 54% of patients. Among the 12 patients who had available follow-up at 450 days, 8 (67%) had a complete response. While 9/52 patients experienced a serious adverse event, none were deemed directly treatment-related per the Data Safety Monitoring Board.18


Enfortumab Vedotin

Enfortumab vedotin (EV) is a Nectin-4 targeted antibody-drug conjugate. Nectin-4 is highly expressed on bladder tumor cells, making it an attractive target for such agents. Systemic use of EV has previously demonstrated an overall survival benefit in the 3rd line setting for patients with locally advanced or metastatic urothelial carcinoma, who had previously received platinum-based therapy and a PD-1 or PD-L1 inhibitor (EV-301).19 Based on its demonstrated benefit in locally advanced/metastatic urothelial carcinoma, EV is currently being evaluated in earlier settings. EV-104 (NCT05014139) is a phase 1, open-label, multicenter, dose-escalation, and dose-expansion study of intravesical EV in adults with high-risk BCG-unresponsive NMIBC (CIS +/- papillary disease) who are ineligible for or refuse radical cystectomy. The primary study objectives are to evaluate the safety and tolerability of intravesical EV and determine the maximum-tolerated and recommended phase II doses of intravesical EV.

Similar in concept to BCG and intravesical chemotherapy regimens, the EV-104 treatment regimen will include an induction phase, whereby patients will receive intravesical EV weekly for 6 weeks followed by monthly maintenance for a total of 9 additional EV doses. Patients will undergo cystoscopy and cytology every 3 months and annual upper tract imaging.

figure-9-intravesical-chemo.jpg

The study is currently enrolling in the United States (since January 2022) with additional sites planned in Canada and Europe, including the UK.

Erdafitinib

Erdafitinib is an oral selective pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor that is approved for locally advanced or metastatic urothelial carcinoma in adults with FGFR3/2 alterations who have progressed during or after at least one line of platinum-containing chemotherapy.20 THOR-2 is a multi-cohort, phase II trial of erdafitinib in patients with high-risk NMIBC, with Cohort 2 including patients with BCG-unresponsive CIS (+/- papillary disease) and FGFR3/2 alterations. In this cohort, patients received continuous oral erdafitinib 6 mg once daily.

Interim results were presented at ASCO GU 2023 by Dr. James Catto. At time of presentation, Cohort 2 had enrolled 10 patients with a median age of 72 years. The complete response rates at the 1st (Cycle 3, Day 1) and 2nd evaluations (Cycle 6, Day 1) were 100% and 75%, respectively. At a median follow-up of 10 months, the median duration of response was 3.0 months. Grade 3 or worse treatment-related adverse events occurred in 3 patients (30%), and included dry mouth, stomatitis, nail disorder, onychomadesis, acute kidney injury, chronic kidney disease, sepsis, and hypotension. One patient discontinued treatment due to adverse events. There were no treatment-related deaths.


Conclusions

Intravesical chemotherapeutic agents have emerged as promising treatment options for patients with BCG unresponsive NMIBC. Given its ease of administration and wide availability, the intravesical combination of gemcitabine plus docetaxel has emerged as one of the most commonly used treatments in this setting in clinical practice. TAR-200, via a local sustained release of gemcitabine, demonstrates excellent early response rates in SunRISE-1. These agents add to the growing armamentarium in the BCG unresponsive disease space with future regulatory approvals by the FDA contingent on further follow-up of current and future studies of these agents.

table-1-intravesical-chemo.jpg 

Published September 2023
Written by: Rashid K. Sayyid, MD, MSc University of Toronto Toronto, ON and Zachary Klaassen, MD, MSc Medical College of Georgia Augusta, Georgia, USA
References:
  1. EAU Guidelines: Non-muscle-invasive Bladder Cancer. https://uroweb.org/guidelines/non-muscle-invasive-bladder-cancer. Accessed on July 30, 2023.
  2. Sylvester RJ, Brausi MA, Kirkels WJ, et al. Long-term efficacy results of EORTC genito-urinary group randomized phase 3 study 30911 comparing intravesical instillations of epirubicin, bacillus Calmette-Guerin, and bacillus Calmette-Guerin plus isoniazid in patients with intermediate- and high-risk stage Ta T1 urothelial carcinoma of the bladder. Eur Urol. 2010;57(5):766-73.
  3. Schmidt S, Kunath F, Coles B, et al. Intravesical Bacillus Calmette-Guérin versus mitomycin C for Ta and T1 bladder cancer. Cochrane Database Syst Review. 2020;1(1):CD011935.
  4. Babjuk M, Burger M, Comperat EM, et al. European Association of Urology Guidelines on non-muscle-invasive bladder cancer (TaT1 and carcinoma in situ) - 2019 Update. Eur Urol. 2019;76(5):639–57.
  5. FDA approves pembrolizumab for BCG-unresponsive, high-risk non-muscle invasive bladder cancer. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-bcg-unresponsive-high-risk-non-muscle-invasive-bladder-cancer. Accessed on July 30, 2023.
  6. FDA D.I.S.C.O. Burst Edition: FDA approval of Adstiladrin (nadofaragene firadenovec-vncg) for patients with high-risk Bacillus Calmette-Guérin unresponsive non-muscle invasive bladder cancer with carcinoma in situ with or without papillary tumors. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-disco-burst-edition-fda-approval-adstiladrin-nadofaragene-firadenovec-vncg-patients-high-risk#:~:text=On%20December%2016%2C%202022%2C%20the,with%20or%20without%20papillary%20tumors. Access on July 30, 2023.
  7. Boorjian SA, Alemozaffar M, Konety BR, Shore ND, Gomella LG, Kamat AM, et al. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial. Lancet Oncol. 2021;22(1):107–117.
  8. O’Donnell MA, Lilli K, Leopold C, National Bacillus Calmette-Guerin/interferon phase 2 investigator G Interim results from a national multicenter phase II trial of combination bacillus Calmette-Guerin plus interferon alfa-2b for superficial bladder cancer. J Urol. 2004;172(3):888–93.
  9. Steinberg RL, Thomas LJ, Brooks N, et al. Multi-Institution Evaluation of Sequential Gemcitabine and Docetaxel as Rescue Therapy for Nonmuscle Invasive Bladder Cancer. J Urol. 2020;203(5):902-9.
  10. Chevuru PT, McElree IM, Mott SL, et al. Long-term follow-up of sequential intravesical gemcitabine and docetaxel salvage therapy for non-muscle invasive bladder cancer. Urol Oncol. 2023;41(3):148.e1-7.
  11. Daneshmand S, van der Heijden MS, Jacob JM, et al. LBA02-03 FIRST RESULTS FROM SunRISE-1 IN PATIENTS WITH BCG UNRESPONSIVE HIGH-RISK NON–MUSCLE-INVASIVE BLADDER CANCER RECEIVING TAR-200 IN COMBINATION WITH CETRELIMAB, TAR-200, OR CETRELIMAB ALONE. J Urol. 2023;209(Suppl 4):e1187.
  12. Witjes JA, Hendricksen K, Gofrit O, Risi O, Nativ O. Intravesical hyperthermia and mitomycin-C for carcinoma in situ of the urinary bladder: experience of the European Synergo® working party. World J Urol. 2009;27:319-24.
  13. Van Valenberg FJP, Kajtazovic A, Canepa G, et al. Intravesical Radiofrequency-Induced Chemohyperthermia for Carcinoma in Situ of the Urinary Bladder: A Retrospective Multicentre Study. Bladder Cancer. 2018;4(4):365-76.
  14. De Jong JJ, Hendricksen K, Rosier M, Mostafid H, Boormans JL. Hyperthermic Intravesical Chemotherapy for BCG Unresponsive Non-Muscle Invasive Bladder Cancer Patients. Bladder Cancer. 2018;4(4):395-401.
  15. Tan WP, Plata Bello A, Garcia Alvarez C, et al. A Multicenter Study of 2-year Outcomes Following Hyperthermia Therapy with Mitomycin C in Treating Non-Muscle Invasive Bladder Cancer: HIVEC-E. Bladder Cancer. 2022;8(4):379-93.
  16. Alzeibak R, Mishchenko TA, Shilyagina NY, et al. Targeting immunogenic cancer cell death by photodynamic therapy: past, present and future. J Immunother Cancer. 2021;9:e001926.
  17. Meng Z, Zhou X, Xu J, et al. Light-triggered in situ gelation to enable robust photodynamic-immunotherapy by repeated stimulations. Adv Mater. 2019;31:e1900927.
  18. Kulkarni GS, Richards KA, Black PC, et al. A phase II clinical study of intravesical photo dynamic therapy in patients with BCG-unresponsive NMIBC (interim analysis). J Clin Oncol. 2023;6(Suppl):528.
  19. Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med 2021;384:1125-35.
  20. Loriot Y, Necchi A, Park SH, et al. Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2019;381:338-48.

Prostate Radiotherapy for De Novo, Low Volume Metastatic Hormone Sensitive Prostate Cancer: Is There Benefit?

The metastatic hormone-sensitive prostate cancer (mHSPC) disease space has seen the emergence of doublet and triplet therapy systemic treatment options, with current guidelines recommending the doublet combination of androgen deprivation therapy (ADT) plus an androgen receptor signaling inhibitor (ARSI; e.g., abiraterone) or ADT + ARSI + docetaxel.1 While systemic therapy remains the backbone of treatment for patients with de novo mHSPC, there has been a long-standing interest in evaluating the benefit of treatment of the primary disease site.
Written by: Rashid Sayyid, MD, MSc and Zachary Klaassen, MD, MSc
References:
  1. Schaeffer EM, Srinivas S, Adra A, et al. NCCN Guidelines® Insights: Prostate Cancer, Version 1.2023. J Natl Compr Canc Netw. 2022;20(12):1288-1298.
  2. Bossi A, Foulon S, Maldonado X, et al. Prostate irradiation in men with de novo, low-volume, metastatic, castration-sensitive prostate cancer (mCSPC): Results of PEACE-1, a phase 3 randomized trial with a 2x2 design. J Clin Oncol. 2023;41(17):Suppl.
  3. Boeve LMS, Hulshof MCCM, Vis AN, et al. Effect on Survival of Androgen Deprivation Therapy Alone Compared to Androgen Deprivation Therapy Combined with Concurrent Radiation Therapy to the Prostate in Patients with Primary Bone Metastatic Prostate Cancer in a Prospective Randomised Clinical Trial: Data from the HORRAD Trial. Eur Urol. 2019;75(3):410-418.
  4. Parker CC, James ND, Brawley CD, et al. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. Lancet. 2018;392(10162):2353-2366.
  5. Parker CC, James ND, Brawley CD, et al. Radiotherapy to the prostate for men with metastatic prostate cancer in the UK and Switzerland: Long-term results from the STAMPEDE randomised controlled trial. PLoS Medicine. 2022;19(6):e1003998.
  6. Sweeney CJ, Chen Y, Carducci M, et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. N Engl J Med. 2015;373:737-746.
  7. James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2016;387(10024):1163-1177.
  8. Fizai K, Foulon S, Carles J, et al. Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 × 2 factorial design. Lancet 2022;399(10336):1695-1707.

 

The Current Treatment Landscape of BCG-unresponsive Non-Muscle Invasive Bladder Cancer: N-803 and Viral/Bacterial-Based Therapies

Introduction


Intravesical Bacillus Calmette-Guerin (BCG) currently remains the standard-of-care, guideline recommended treatment of choice in the adjuvant setting for intermediate- and high-risk non-muscle invasive bladder cancer (NMIBC) due to its ability to reduce the risk of disease recurrence and disease progression.1-3 However, despite adequate BCG, up to 50% of patients develop a BCG-refractory, relapsing, or failure state.4
Written by: Rashid K. Sayyid, MD, MSc, University of Toronto, Toronto, ON and Zachary Klaassen, MD, MSc, Medical College of Georgia, Augusta, Georgia, USA
References:
  1. EAU Guidelines: Non-muscle-invasive Bladder Cancer.
  2. Sylvester RJ, Brausi MA, Kirkels WJ, et al. Long-term efficacy results of EORTC genito-urinary group randomized phase 3 study 30911 comparing intravesical instillations of epirubicin, bacillus Calmette-Guerin, and bacillus Calmette-Guerin plus isoniazid in patients with intermediate- and high-risk stage Ta T1 urothelial carcinoma of the bladder. Eur Urol. 2010;57(5):766-73.
  3. Schmidt S, Kunath F, Coles B, et al. Intravesical Bacillus Calmette-Guérin versus mitomycin C for Ta and T1 bladder cancer. Cochrane Database Syst Review. 2020;1(1):CD011935.
  4. Babjuk M, Burger M, Comperat EM, et al. European Association of Urology Guidelines on non-muscle-invasive bladder cancer (TaT1 and carcinoma in situ) - 2019 Update. Eur Urol. 2019;76(5):639–57.
  5. Steinberg R, Bahnson R, Brosman S, et al. Efficacy and Safety of Valrubicin for the Treatment of Bacillus Calmette-Guerin Refractory Carcinoma in Situ of the Bladder. J Urol. 200;163(3):761-7.
  6. Bacillus Calmette-Guérin-unresponsive nonmuscle invasive bladder cancer: developing drugs and biologics for treatment guidance for industry. 2018.
  7. FDA approves pembrolizumab for BCG-unresponsive, high-risk non-muscle invasive bladder cancer.
  8. FDA D.I.S.C.O. Burst Edition: FDA approval of Adstiladrin (nadofaragene firadenovec-vncg) for patients with high-risk Bacillus Calmette-Gu√©rin unresponsive non-muscle invasive bladder cancer with carcinoma in situ with or without papillary tumors. 
  9. Kates M, Matoso A, Choi W, et al. Adaptive Immune Resistance to Intravesical BCG in Non–Muscle Invasive Bladder Cancer: Implications for Prospective BCG-Unresponsive Trials. Clin Cancer Res. 2020;26(4):882-91.
  10. Balar AV, Kamat AM, Kulkarni GS, et al. Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study. Lancet Oncol. 2021;22(7):919-30.
  11. Necchi A, Roumiguié M, Esen AA, et al. Pembrolizumab (pembro) monotherapy for patients (pts) with high-risk non–muscle-invasive bladder cancer (HR NMIBC) unresponsive to bacillus Calmette–Guérin (BCG): Results from cohort B of the phase 2 KEYNOTE-057 trial. J Clin Oncol. 2023;41(Supp 6):LBA442.
  12. Li R, Sexton WJ, Dhillon J, et al. A Phase 2 Study of Durvalumab for Bacillus Calmette-Guerin (BCG) Unresponsive Urothelial Carcinoma In Situ of the Bladder. Clin Cancer Res. 2023.
  13. Chamie K, Chang SS, Kramolowsky E, et al. IL-15 Superagonist NAI in BCG-Unresponsive Non–Muscle-Invasive Bladder Cancer. N Engl J Med Evid. 2023;2(1).
  14. O’Donnell MA, Lilli K, Leopold C, National Bacillus Calmette-Guerin/interferon phase 2 investigator G Interim results from a national multicenter phase II trial of combination bacillus Calmette-Guerin plus interferon alfa-2b for superficial bladder cancer. J Urol. 2004;172(3):888–93.
  15. Boorjian SA, Alemozaffar M, Konety BR, Shore ND, Gomella LG, Kamat AM, et al. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial. Lancet Oncol. 2021;22(1):107–117.
  16. Friedlander TW, Weinberg VK, Yeung A, et al. Activity of intravesical CG0070 in Rb-inactive superficial bladder cancer after BCG failure: Updated results of a phase I/II trial. J Clin Oncol. 2012 (Supplement).
  17. Packiam VT, Lamm DL, Barocas DA, et al. An open label, single-arm, phase II multicenter study of the safety and efficacy of CG0070 oncolytic vector regimen in patients with BCG-unresponsive non-muscle-invasive bladder cancer: Interim results. Urol Oncol. 2018;36(10):440-7.
  18. Li R, Steinberg GD, Uchio EM, et al. CORE1: Phase 2, single-arm study of CG0070 combined with pembrolizumab in patients with nonmuscle-invasive bladder cancer (NMIBC) unresponsive to bacillus Calmette-Guerin (BCG). J Clin Oncol. 2022;40(Suppl):4597.
  19. Bandari JJZ, Belani K, Brown E, Metcalf M, Nanayakkara N. Phase 1a/b safety study of intravesical instillation of TARA-002 in adults with high-grade non-muscle invasive bladder cancer (ADVANCED-1). J Clin Oncol. 2022;40(6):TPS4620.
  20. Sun W, Bandari J, Zummo J, et al. Phase 1b/2 dose expansion, open-label study to evaluate safety and anti-tumor activity of intravesical instillation of TARA-002 in adults with high-grade non-muscle invasive bladder cancer. J Clin Oncol. 2023;41(Suppl):TPS4618.
  21. Kowalski M, Guindon J, Brazas L, et al. A phase II study of oportuzumab monatox: an immunotoxin therapy for patients with noninvasive urothelial carcinoma in situ previously treated with bacillus Calmette-Guérin. J Urol. 2012;188(5):1712-8.
  22. Shore N, O’Donnell M, Keane T, et al. PD03-02: Phase 3 Results of Vicinium in BCG-Unresponsive Non-Muscle Invasive Bladder Cancer. J Urol. 2020;Supp 4:e72.

House Energy and Commerce – Oversight and Investigations Subcommittee Hearing: “MACRA Checkup: Assessing Implementation and Challenges that Remain for Patients and Doctors”

On June 22, 2023, the Oversight and Investigations Subcommittee of the House Energy and Commerce Committee hosted a hearing entitled, “MARCA Checkup: Assessing Implementation and Challenges that Remain for Patients and Doctors.”

The Treatment Landscape of Metastatic Urothelial Carcinoma: First-Line Systemic Therapy in Cisplatin Eligible Patients

Introduction


Metastatic urothelial carcinoma is associated with a poor prognosis, with a median overall survival of less than two years. To date, combination platinum-based chemotherapy remains the standard of care first line treatment for these patients who are suitable for chemotherapy. This Center of Excellence article will assess criteria for determining cisplatin chemotherapy eligibility, review the landmark trials that established cisplatin-based chemotherapy as the standard of care for first-line treatment, and review recent data for avelumab maintenance therapy among patients that did not progress on first-line chemotherapy.
Written by: Zachary Klaassen, MD, MSc Associate Professor of Urology Urologic Oncologist Medical College of Georgia, Georgia Cancer Center Augusta, GA and Rashid Sayyid, MD, MSc Urologic Oncology Fellow University of Toronto Toronto, Ontario, Canada
References:
  1. Galsky MD, Hahn NM, Rosenberg J, et al. Treatment of patients with metastatic urothelial cancer "unfit" for Cisplatin-based chemotherapy. J Clin Oncol. 2011;29: 2432-2438.
  2. Sternberg CN, Yagoda A, Scher HI, et al. Preliminary results of M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) for transitional cell carcinoma of the urothelium. J Urol. 1985;133: 403-407.
  3. Sternberg CN, Yagoda A, Scher HI, et al. Methotrexate, vinblastine, doxorubicin, and cisplatin for advanced transitional cell carcinoma of the urothelium. Efficacy and patterns of response and relapse. Cancer. 1989;64: 2448-2458.
  4. Bajorin DF, Dodd PM, Mazumdar M, et al. Long-term survival in metastatic transitional-cell carcinoma and prognostic factors predicting outcome of therapy. J Clin Oncol. 1999;17: 3173-3181.
  5. von der Maase H, Hansen SW, Roberts JT, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000;18: 3068-3077.
  6. Sternberg CN, de Mulder PH, Schornagel JH, et al. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol no. 30924. J Clin Oncol. 2001;19: 2638-2646.
  7. Sternberg CN, de Mulder P, Schornagel JH, et al. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer. 2006;42: 50-54.
  8. Lee YS, Ha MS, Tae JH, et al. Gemcitabine-cisplatin versus MVAC chemotherapy for urothelial carcinoma: a nationwide cohort study. Sci Rep. 2023;13: 3682.
  9. Powles T, Park SH, Voog E, et al. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2020;383: 1218-1230.
  10. Powles T, Park SH, Caserta C, et al. Avelumab First-Line Maintenance for Advanced Urothelial Carcinoma: Results From the JAVELIN Bladder 100 Trial After >/=2 Years of Follow-Up. J Clin Oncol. 2023;41: 3486-3492.
  11. Powles T, Sridhar SS, Loriot Y, et al. Avelumab maintenance in advanced urothelial carcinoma: biomarker analysis of the phase 3 JAVELIN Bladder 100 trial. Nat Med. 2021;27: 2200-2211.

Habits That Can Affect Your Bladder

Common Bladder Irritants Found in Foods and Drinks

Certain foods, liquids and beverages, medications and even herbs can “trigger” your bladder symptoms. Their effect on the bladder is not always understood and the same food or liquid may affect different people and their bladders in different ways. Check the lists found here to see if any of them are adding to your symptoms. If you find one, stop them for a few days to see if your bladder symptoms improve. Then introduce it back and see if you notice any changes.

Novel Treatment Options for BCG Naïve Non-Muscle Invasive Bladder Cancer: Immune Priming and Immune Check Point Inhibitors

Introduction

Immune checkpoint inhibitors have emerged as a guideline-recommended first line treatment option for patients with cisplatin-ineligible, metastatic urothelial carcinoma of the bladder and as second line therapy for patients with metastatic disease progressing during, or after, platinum-based combination chemotherapy.1 Pembrolizumab, a Programmed Death-1 (PD-1) inhibitor, has been recently approved by the US Food and Drug Administration for the treatment of patients with Bacillus Calmette Guerin (BCG)-resistant non-muscle invasive bladder cancer (NMIBC), based on the results of the KEYNOTE-057 trial.2,3

Given that patients with NMIBC receiving adjuvant BCG post-TURBT have estimated risks of disease recurrence and progression of 40% and 10%, respectively,4 the BCG naïve NMIBC space may provide an opportunity to move these agents up even further along the bladder cancer disease spectrum. In this Center of Excellence article, we will summarize the current state of the evidence for ongoing trials evaluating immune check point inhibitors and other immune priming interventions in combination with BCG for the treatment of BCG naïve NMIBC.

Pembrolizumab + BCG

Previous studies have demonstrated that programmed cell death ligand 1 (PD-L1) expression is significantly increased in BCG-induced bladder granulomata of patients with BCG unresponsive disease.5 As such, it has been hypothesized that the addition of a PD-1 inhibitor, such as pembrolizumab, may overcome this potential underlying mechanism of resistance.

The combination of pembrolizumab + BCG has previously been evaluated in the setting of a phase I trial for patients with BCG unresponsive NMIBC. This combination was determined to be relatively safe, and the 13 evaluable patients had a 3-month complete response rate of 69%.6

KEYNOTE-676 is a randomized, comparator-controlled trial evaluating the efficacy and safety of pembrolizumab + BCG in patients with high-risk NMIBC (T1, CIS, high grade Ta) who underwent cystoscopy/transurethral resection of bladder tumor ≤12 weeks before randomization and had not received BCG within the preceding two years. Patients will be randomly assigned 1:1:1 to receive:

  • Pembrolizumab 400 mg IV every 6 weeks + BCG reduced maintenance (≤ 6 months)
  • Pembrolizumab 400 mg IV every 6 weeks + BCG full maintenance (≤ 18 months)
  • BCG monotherapy with BCG full maintenance

The trial schema for KEYNOTE-676 cohort B is as follows:
figure-1-BCGNaive-Immune-Priming.jpg

The primary endpoint for this trial is event-free survival, defined as the time from random assignment to the first occurrence of any of the following:

  • High-grade Ta, CIS, or any T1 disease of the bladder
  • High-risk disease (high-grade Ta, CIS, or ≥T1) of the urethra or upper tract
  • Locally advanced/metastatic disease determined by blinded independent central review
  • Death from any cause

The secondary endpoints will include complete response rate by blinded independent central review, duration of response, disease-specific survival, time to cystectomy, overall survival, and safety.7 As follows is a geographical representation of the countries currently enrolling patients in KEYNOTE-676:

figure-2-BCGNaive-Immune-Priming.jpg

Additionally, a single arm, phase II trial (NCT03504163) from the Memorial Sloan Kettering Cancer Center is evaluating the combination of BCG + pembrolizumab in patients with high-risk T1 bladder cancer, with an additional exploratory cohort of patients with upper tract disease. This study will plan to enroll 37 patients, who will receive pembrolizumab 400 mg IV at 6-week intervals (total 9 doses), with BCG (TICE strain, 50 mg) administered once weekly for 6 weeks as induction, followed by maintenance consistent with standard clinical practice. BCG will be started on week 3 after the first infusion of pembrolizumab to allow for the initial priming of T cells to further enhance the effects of BCG treatment. The primary outcome is the proportion of patients who remain free of high-grade disease recurrences at 6 months post-treatment initiation.8

Atezolizumab + BCG

BladderGATE

BladderGATE (NCT04134000) is a phase Ib-II trial evaluating the safety and efficacy of atezolizumab (anti-PD-L1) + BCG in patients with high-risk NMIBC, who are either BCG-naïve or had not received BCG in the preceding two years. Patients in this trial will receive either:

  • Induction BCG with 1 instillation every week + IV atezolizumab 1,200 mg every 3 weeks (Dose level 0)
  • Induction BCG with ½ instillation every week + IV atezolizumab 1,200 mg every 3 weeks (Dose level -1)

Following induction, BCG will be administered at weeks 13-15, 25-27, and 49-51, with atezolizumab concurrently administered for up to 1 year. Patients were accrued to each dose level in cohorts of 10 patients until the maximum tolerated dose is achieved (dose at which < 4 out of 10 patients experience dose-limiting toxicity). The interim safety results were recently presented at ASCO 2023. This analysis included 34 patients, with no dose-limiting toxicities reported in the first 10 patients included at dose level 0. The most frequent grade 3-4 adverse events were:

  • Asthenia (9%)
  • Myocarditis (3%)
  • Immune-mediated hepatitis (3%)
  • Hyponatremia (3%)
  • Encephalopathy (3%)
  • Guillain-Barre syndrome (3%)

Two patients discontinued the study treatment due to immune-mediated Grade 3 hepatitis and pneumonitis, respectively.9

ALBAN

ALBAN (AFU-GETUG 37; NCT03799835) is a phase III trial across 30 centers in France evaluating the efficacy and safety of atezolizumab given in combination with BCG versus BCG alone in patients with BCG naïve, high-risk NMIBC (T1, high-grade, and/or CIS). Eligible patients will be randomized 1:1 to:

  • Arm A: BCG alone with six weeks induction followed by three weekly maintenance instillations at 3, 6, and 12 months
  • Arm B: BCG + atezolizumab (1,200 mg IV every 3 weeks for up to 1 year)

The primary endpoint is recurrence-free survival in the intent-to-treat population, with secondary efficacy endpoints of overall survival, progression-free survival, complete response, disease worsening, quality of life, and safety outcomes. Study enrollment began in December 2018 with a target of 614 patients.10

Durvalumab + BCG

POTOMAC (NCT03528694) is an open label, multicenter, randomized trial evaluating the combination of durvalumab (anti-PD-L1) and BCG in BCG-naïve patients with high-risk NMIBC (any high-grade disease, T1, CIS, LG Ta if >3 cm, recurrent, and multifocal). This trial will randomize 1,018 patients to:

  • BCG induction + maintenance for 24 months
  • BCG induction + maintenance + durvalumab (1,500 mg every 4 weeks for 13 cycles)
  • BCG induction only (no maintenance) + durvalumab

The study design is as follows:
figure-3-BCGNaive-Immune-Priming.jpg

The primary study endpoint is disease-free survival, with secondary endpoints including the proportion of patients alive and disease-free at 24 months, 5-year overall survival, pharmacokinetics, immunogenicity, safety, tolerability, and health-related quality of life.11

Sasanlimab + BCG

Sasanlimab is an anti-PD-1 monoclonal antibody that has demonstrated an acceptable safety profile and promising clinical activity in patients with locally advanced or metastatic urothelial carcinoma, within the context of a phase 1 trial.12 The phase 3 CREST study (NCT04165317) Cohort A will evaluate subcutaneous injection sasanlimab in patients with BCG naive NMIBC. Patients in this cohort will be randomized to one of three arms:

  • Arm A: Sasanlimab + BCG induction + maintenance
  • Arm B: Sasanlimab + BCG induction only
  • Arm C: BCG induction + maintenance

This trial will assess for between-arm differences in event-free, disease-specific, and overall survivals, complete response rate, adverse events/safety profile, and health-related quality of life.13 Of note, On August 31, 2022, the Sponsor announced the discontinuation of enrollment to Part B (Cohort B), which enrolled participants with BCG unresponsive NMIBC. The decision to discontinue enrollment to Part B (Cohort B) was not made for safety reasons.14

Immune Priming: Intradermal BCG

The PRIME trial (SWOG S1612) is evaluating whether intradermal BCG inoculation may potentiate the immune effects of subsequent intravesical BCG instillations. This hypothesis was recently tested in a single arm trial that demonstrated that percutaneous BCG administered 21 days prior to intravesical instillation in patients with high-risk NMIBC boosted BCG-specific immunity at 3 months and increased the activation status of in vitro expanded circulating NK and γδ T cells and their cytotoxicity against bladder cancer cells.15

In the PRIME trial, the Tokyo BCG strain is being used for both intradermal inoculation and intravesical instillation in a three-arm design with TICE strain BCG also used as a standard of care comparator. This study was designed to test:

  • The comparitive superiority between intravesical Tokyo strain BCG when combined with intradermal inoculation as compared to intravesical alone (arms 2 and 3)
  • The non-inferiority of intravesical Toyko strain alone to intravesical TICE strain (arms 1 and 2).
    • TICE strain is currently the only strain that is FDA approved and in production in the USA (Armond-Frappier and Connaught are also FDA approved, but not currently in production). As such, if the Tokyo strain is found to be non-inferior to TICE, this may facilitate its subsequent FDA approval and increased the availability of additional BCG strains during the current shortage

The study design is as follows:
figure-4-BCGNaive-Immune-Priming.jpg

This trial has now fully accrued and is awaiting readout in the nearby future.

Conclusions

Numerous ongoing trials are evaluating the combination of BCG and an immune checkpoint inhibitor for patients with BCG naïve NMIBC. By inhibiting the PD-1/PD-L1 axis, it is hypothesized that these agents may help overcome underlying mechanisms of resistance inherent to BCG-resistant strains, and thus improve on the historic recurrence and progression rates observed with BCG treatment alone. Many of these trials have completed accrual, and we await the results of these combinatory trials in the upcoming years.

Published August 2023
Written by: Rashid K. Sayyid, MD, MSc, University of Toronto, Toronto, ON & Zachary Klaassen, MD, MSc, Medical College of Georgia, Augusta, Georgia, USA
References:
  1. EAU Guidelines: Non-muscle-invasive Bladder Cancer. https://uroweb.org/guidelines/non-muscle-invasive-bladder-cancer. Accessed on Aug 6, 2023.
  2. FDA approves pembrolizumab for BCG-unresponsive, high-risk non-muscle invasive bladder cancer. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-bcg-unresponsive-high-risk-non-muscle-invasive-bladder-cancer. Accessed on Aug 6, 2023.
  3. Balar AV, Kamat AM, Kulkarni GS, et al. Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study. Lancet Oncol. 2021;22(7):919-30.
  4. Sylvester RJ, Brausi MA, Kirkels WJ, et al. Long-term efficacy results of EORTC genito-urinary group randomized phase 3 study 30911 comparing intravesical instillations of epirubicin, bacillus Calmette-Guerin, and bacillus Calmette-Guerin plus isoniazid in patients with intermediate- and high-risk stage Ta T1 urothelial carcinoma of the bladder. Eur Urol. 2010;57(5):766-73.
  5. Inman BA, Sebo TJ, Frigola X, et al. PD-L1 (B7–H1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata: associations with localized stage progression. Cancer. 2007;109(8):1499-505
  6. Alanee S, Sana S, El-Zawahry A, et al. Phase I trial of intravesical Bacillus Calmette-Guérin combined with intravenous pembrolizumab in recurrent or persistent high-grade non-muscle-invasive bladder cancer after previous Bacillus Calmette-Guérin treatment. World J Urol. 2021;39(10):3807-13.
  7. Kamat AM, Shariat S, Steinberg GD, et al. Randomized comparator-controlled study evaluating efficacy and safety of pembrolizumab plus Bacillus Calmette-Guérin (BCG) in patients with high-risk nonmuscle-invasive bladder cancer (HR NMIBC): KEYNOTE-676 cohort B. J Clin Oncol. 2022;40(Suppl 6): TPS597
  8. ClinicalTrials.gov - Pembrolizumab (MK-3475) and Bacillus Calmette-Guérin (BCG) as First-Line Treatment for High-Risk T1 Non-Muscle-Invasive Bladder Cancer (NMIBC) and High-Grade Non-Muscle-Invasive Upper Tract Urothelial Carcinoma (NMI-UTUC)].  
  9. Castellano D, de Velasco G, Carretero-Gonzalez A, et al. Atezolizumab + intravesical BCG (bacillus Calmette-Guerin) upfront combination in high risk non–muscle- invasive bladder cancer (NMIBC) patients: Safety interim report of BladderGATE phase I-II study. J Clin Oncol. 2023;41(Supp 16):e16590.
  10. Roupret M, Neuzillet Y, Bertaut A, et al. ALBAN: An open label, randomized, phase III trial, evaluating efficacy of atezolizumab in addition to one year BCG (Bacillus Calmette-Guerin) bladder instillation in BCG-naive patients with high-risk nonmuscle invasive bladder cancer (AFU-GETUG 37). J Clin Oncol. 2019;37(Suppl 15):TPS4589.
  11. De Santis M, Abdrashitov R, Hegele A, et al. A phase III, randomized, open-label, multicenter, global study of durvalumab and bacillus calmette-guérin (BCG) versus BCG alone in high-risk, BCG-naïve non-muscle-invasive bladder cancer (NMIBC) patients (POTOMAC). J Clin Oncol. 2019;37(Suppl 7):TPS500.
  12. Shore ND, Powles T, Bedke J, et al. A phase 3 study of the subcutaneous programmed cell death protein 1 inhibitor sasanlimab as single agent for patients with bacillus Calmette-Guérin, unresponsiv,e high-risk, non-muscle invasive bladder cancer: CREST Study Cohort B. J Clin Oncol. 2022;40(Suppl 16):40.
  13. ClinicalTrials.gov. A Study of Sasanlimab in People With Non-muscle Invasive Bladder Cancer (CREST). https://classic.clinicaltrials.gov/ct2/show/NCT04165317. Access on Aug 6, 2023.

  14. Clinicaltrials.gov. Available at: https://www.clinicaltrials.gov/study/NCT04165317?intr=sasanlimab&rank=8 (Accessed: 26 April 2024)

  15. Ji N, Mukherjee N, Morales EE, et al. Percutaneous BCG enhances innate effector antitumor cytotoxicity during treatment of bladder cancer: a translational clinical trial. Oncoimmunology. 2019;8(8):1614857.

How to Do Pelvic Floor Muscle Exercises

WHAT ARE THE PELVIC FLOOR MUSCLES?
Your pelvic floor muscles provide support to your bladder, and rectum and, in women, the vagina and the uterus. These muscles are like a sling or hammock in the bottom of your pelvis which is why they are called pelvic floor muscles. If they weaken or are damaged, they do not support pelvic organs and may cause bladder control problems. Keeping the muscles strong by training them, can help prevent urine leakage. You can make these muscles stronger by doing exercises (often called Kegel exercises).

Novel Treatment Options for BCG Naïve Non-Muscle Invasive Bladder Cancer: Intravesical Chemotherapy

Introduction

Bacillus Calmette Guerin (BCG) is currently guideline-recommended in the adjuvant setting for patients with intermediate or high-risk non-muscle invasive bladder cancer (NMIBC).1 This is based on the results of numerous randomized clinical trials and meta-analyses demonstrating its ability to reduce the rates of disease recurrence and progression, compared to transurethral resection of bladder tumor (TURBT) alone or other adjuvant therapies.2-5

Written by: Rashid K. Sayyid, MD, MSc University of Toronto Toronto, ON & Zachary Klaassen, MD, MSc Medical College of Georgia Augusta, Georgia, USA
References:
  1. EAU Guidelines: Non-muscle-invasive Bladder Cancer. https://uroweb.org/guidelines/non-muscle-invasive-bladder-cancer. Accessed on Aug 5, 2023.
  2. Sylvester RJ, Brausi MA, Kirkels WJ, et al. Long-term efficacy results of EORTC genito-urinary group randomized phase 3 study 30911 comparing intravesical instillations of epirubicin, bacillus Calmette-Guerin, and bacillus Calmette-Guerin plus isoniazid in patients with intermediate- and high-risk stage Ta T1 urothelial carcinoma of the bladder. Eur Urol. 2010;57(5):766-73.
  3. Schmidt S, Kunath F, Coles B, et al. Intravesical Bacillus Calmette-Guérin versus mitomycin C for Ta and T1 bladder cancer. Cochrane Database Syst Review. 2020;1(1):CD011935.
  4. Malmstrom PU, Sylvester RJ, Crawford DE, et al. An individual patient data meta-analysis of the long-term outcome of randomised studies comparing intravesical mitomycin C versus bacillus Calmette-Guerin for non-muscle-invasive bladder cancer. Eur Urol. 2009;56(2):247-56.
  5. Bohle A, Jocham D, Bock PR. Intravesical bacillus Calmette-Guerin versus mitomycin C for superficial bladder cancer: a formal meta-analysis of comparative studies on recurrence and toxicity. J Urol. 2003;169(1):90-5.
  6. Oresta B, et al. Sci Transl Med. Jan 6;13(575):eaba6110 Clinical trial information: EudraCT 2021-003751-42_studio ICH-013 (MMC).
  7. Di Stasi SM, Giannantoni A, Giurioli A, et al. Sequential BCG and electromotive mitomycin versus BCG alone for high-risk superficial bladder cancer: a randomised controlled trial. Lancet Oncol. 2006;7:43-51.
  8. Solsona E, Madero R, Chantada V, et al. Sequential combination of mitomycin C plus bacillus Calmette-Guérin (BCG) is more effective but more toxic than BCG alone in patients with non-muscle-invasive bladder cancer in intermediate- and high-risk patients: final outcome of CUETO 93009, a randomized prospective trial. Eur Urol. 2015;67(3):508-16.
  9. Kaasinen E, Wijkstrom H, Rintala E, et al. Seventeen-year follow-up of the prospective randomized Nordic CIS study: BCG monotherapy versus alternating therapy with mitomycin C and BCG in patients with carcinoma in situ of the urinary bladder. Scand J Urol. 2016;50(5):360-8.
  10. De Nunzio C, Leonardo C, Carbone A, et al. MP63-12 THE EFFECTS OF SEQUENTIAL MITOMYCIN AND BACILLUS CALMETTE-GUÉRIN TREATMENT VERSUS BACILLUS CALMETTE-GUÉRIN MONOTHERAPY IN PATIENTS WITH HIGH-RISK NON-MUSCLE INVASIVE BLADDER CANCER: MITO-BCG (EUDRACT-2017-004540-37). J Urol. 2023;209(Suppl 4):e876.
  11. Jagannath C, Lindsey DR, Dhandayuthapani S, et al.. Autophagy enhances the efficacy of BCG vaccine by increasing peptide presentation in mouse dendritic cells. Nat Med. 2009;15:267–76.
  12. Ji N, Mukherjee N, Reyes RM, et al. Rapamycin enhances BCG-specific γδ T cells during intravesical BCG therapy for non-muscle invasive bladder cancer: a randomized, double-blind study. J Immunother Cancer. 2021;9(3):e001941.
  13. Steinberg RL, Thomas LJ, Brooks N, et al. Multi-Institution Evaluation of Sequential Gemcitabine and Docetaxel as Rescue Therapy for Nonmuscle Invasive Bladder Cancer. J Urol. 2020;203(5):902-9.
  14. McElree IM, Steinberg RL, Mott SL, et al. Comparison of Sequential Intravesical Gemcitabine and Docetaxel vs Bacillus Calmette-Guérin for the Treatment of Patients With High-Risk Non–Muscle-Invasive Bladder Cancer. JAMA Netw Open. 2023;6(2):e230849.
  15. Guerrero-Ramos F, Gonzalez-Padilla DA, Gonzalez-Diaz A, et al. Recirculating hyperthermic intravesical chemotherapy with mitomycin C (HIVEC) versus BCG in high-risk non-muscle-invasive bladder cancer: results of the HIVEC-HR randomized clinical trial. World J Urol. 2022;40(4):999-1004.

Controlling Your Bladder Urges With Bladder Training

Usually, the bladder can hold urine for 4 to 5 hours, then you feel the urge to pee (urinate) and you should be able to walk to the bathroom. But some people will have an overactive bladder and feel a sudden urge to pee that comes on quickly, they may have that “gotta-go” sensation. This is called bladder urgency.

The Path Forward for Telehealth in Medicare

The COVID-19 pandemic brought about a rapid expansion of telehealth services to ensure that patients were able to obtain necessary medical care without exposure to illness. Prior to this point, Medicare was very hesitant to cover telemedicine given lack of evidence regarding quality and cost, as well as effects on outcomes. As the Public Health Emergency (PHE) ended in May 2023, Congress turned to the Medicare Payment Advisory Commission (MedPAC) for an evaluation of the current state of telehealth services, and for recommendations on how to provide payment for telehealth services in the future.

PARP Inhibitor Plus Androgen Receptor Signaling Inhibitor Combinations: Will This Be The Future of mCRPC First-Line Therapy?

Introduction: Despite the approval of numerous agents in this setting, patients with metastatic castrate-resistant prostate cancer (mCRPC) have a poor prognosis, with an estimated median overall survival (OS) of approximately three years with currently approved first-line agents.1-3

Written by: Rashid K. Sayyid, MD MSc & Zachary Klaassen, MD MSc
References:
  1. Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 2013; 368(2):138-48.
  2. Beer TM, Armstrong AJ, Rathkopf D, et al. Enzalutamide in Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer: Extended Analysis of the Phase 3 PREVAIL Study. Eur Urol 2017; 71(2):1 51-4.
  3. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 351(15):1502-12.
  4. George DJ, Sartor O, Miller K, et al. Treatment Patterns and Outcomes in Patients With Metastatic Castration-resistant Prostate Cancer in a Real-world Clinical Practice Setting in the United States. Clin Genitourin Cancer 2020; 18(4):284-94.
  5. De Bono J, Mateo J, Fizazi K, et al. Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med 2020; 382(22): 2091-102.
  6. Abida W, Patnaik A, Campbell D, et al. Rucaparib in Men With Metastatic Castration-Resistant Prostate Cancer Harboring a BRCA1 or BRCA2 Gene Alteration. J Clin Oncol 2020; 38(32): 3763-72.
  7. Fizazi K, Piulats JM, Reaume MN, et al. Rucaparib or Physician’s Choice in Metastatic Prostate Cancer. N Engl J Med 2023; 388: 719-32.
  8. Asim M, Tarish F, Zecchini HI, et al. Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer. Nat Commun 2017; 8: 374.
  9. Schiewer MJ, Goodwin JF, Han S, et al. Dual roles of PARP-1 promote cancer growth and progression. Cancer Discov 2012; 2: 1134-49.
  10. Li L, Karanika S, Yang G, et al. Androgen receptor inhibitor-induced “BRCAness” and PARP inhibition are synthetically lethal for castration-resistant prostate cancer. Sci Signal 2017; 10: eaam7479.
  11. Clarke N, Wiechno P, Alekseev B, et al. Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol 2018; 19: 975-86.
  12. Clarke NW, Armstrong AJ, Thiery-Vuillemin A, et al. Abiraterone and Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med 2022; 1(9).
  13. Clarke NW, Armstrong AJ, Thiery-Vuillemin A, et al. Final overall survival (OS) in PROpel: abiraterone (abi) and olaparib (ola) versus abiraterone and placebo (pbo) as first-line (1L) therapy for metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol 2023; 41(Suppl 6; abstr LBA16).
  14. Chi KN, Rathkopf DE, Smith MR, et al. Niraparib and Abiraterone Acetate for Metastatic Castration-Resistant Prostate Cancer. J Clin Oncol 2023; JCO2201649.
  15. Agarwal N, Azad A, Carles J, et al. Abiraterone and Olaparib for Metastatic Castration-Resistant Prostate Cancer. J Clin Oncol 2023; 41 (Suppl 6; abstr LBA17).

Medicare Advantage: the Who, What, Where, Why… and What’s Next?

Over the past several years, Medicare Advantage (MA) insurance has been heavily criticized by health economists for the large degree of overpayments from Medicare, as well as by patients and physicians for restrictive networks, inconsistent coverage, and often high out-of-pocket costs for patients. Although one may think that MA plans fall under the Medicare/Medicaid umbrella based on the name of these plans, the MA program actually consists of private health plans.

Suprapubic (SP) Urinary Catheter (SPC or SP Tube [SPT])

Background: Suprapubic catheterization (SPC) is placement of a hollow tube, a urinary catheter, into the bladder through a small incision in the avascular midline of the rectus sheath in the lower abdominal wall just above (3 cm) the symphysis of the pubic bone and below the naval. These 2 Figures show an SPC inserted in a female and a male. Like an indwelling urethral catheter (IUC), the catheter is there to drain the bladder and is secured in the bladder by a balloon inflated with fluid.
Written by: Diane K. Newman, DNP, ANP-BC, FAAN
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