The Uromigos Live & Unplugged: New Perspectives on GU Cancer

In a one-of-a-kind event, The Uromigos Live & Unplugged convened global thought leaders in the care of urologic malignancies to examine the current state of disease management, share contrasting views on therapeutic strategies, and predict the future of bladder cancer, prostate cancer, and renal cell carcinoma. Over the course of 1.5 days, the program incorporated gamified presentations and live and in-depth discussions to facilitate new clarity in the field of urologic malignancies. Transcending the confines of a typical meeting, this live event ensured active discussion through multiple channels, including live social media polls, live and remote audience member Q&A, and social media comments integrated directly into the content. Experts challenged each other to generate unique content that could not be reached through any other meeting format.

The meeting, co-hosted by Thomas Powles, MBBS, MRCP, MD, professor of genitourinary oncology at the University of London and director of the Barts Cancer Centre, and Brian Rini, MD, medical oncologist at Vanderbilt Health in Nashville, Tennessee, builds on the success of the weekly Uromigos podcast developed by Drs. Powles and Rini. Regarding the unique format, Dr. Rini, noted, “We set out to create high-quality content through an unconventional approach to limit the didactics and slides and build on our podcast format through panel-based conversations of standard approaches, controversies, and novel drugs relevant to the clinical care of genitourinary cancer patients.”

Bladder Cancer

In the frontline setting of urothelial cancer management, multiple checkpoint inhibitor trials—including IMvigor130, DANUBE, KEYNOTE-361, CheckMate-901, and Nile—have failed to show a significant benefit in improving overall survival.¹ “We have learned that the frontline combinations in metastatic urothelial cancer have not been successful,” said moderator Dr. Powles.

Urologic oncologists are looking to combination data for antibody-drug conjugates with checkpoint inhibitors as a way forward. For example, enfortumab vedotin plus pembrolizumab may be a promising combination in the treatment of patients with urothelial carcinoma who are ineligible for platinum-based chemotherapy.² According to Dr Powles, “Enfortumab vedotin plus pembrolizumab is likely to change practice with ongoing trials like EV-302.” However, at present, chemotherapy remains the standard frontline therapy.

In the adjuvant setting, positive results have been reported, with nivolumab improving disease-free survival in the CheckMate-247 clinical study.³ However, a non-prespecified subgroup analysis found that results were less promising in patients with upper-tract urothelial cancer. Consequently, some urologic oncologists choose gemcitabine plus cisplatin as a treatment of choice over nivolumab, but this practice is controversial. Regarding the results of CheckMate-247, Matthew Galsky, MD, of the Mount Sinai School of Medicine, thinks that “clinical trials are designed to answer a specific question, and this trial asked whether adjuvant nivolumab improved overall survival in the all-comer population and whether it improved disease-free survival in tumors harboring high levels of [programmed death ligand 1 (PD-L1)] expression. Both primary analyses were positive,” Dr. Galsky said, “We should not be relying on subgroup analyses to guide these clinical decisions.”

Though trials regarding checkpoint inhibitors were negative in the frontline setting, oncologists are hopeful about the potential for antibody-drug conjugates in combination with checkpoint inhibitors. Prior biomarkers like PD-L1 expression were disappointing in terms of interobserver reliability, but a new generation of biomarkers in bladder cancer is emerging. “The second generation of biomarkers looks exciting, with [circulating tumor DNA] and [tumor mutation burden] being the most promising,” Dr Powles said. Such biomarkers may help select patients who are most likely to benefit from therapy, informing care and improving outcomes over the next 5 years and beyond.

Prostate Cancer

In the current management of metastatic hormone-sensitive prostate cancer (mHSPC), appropriately identifying patients who are candidates for triplet therapy with dual androgen deprivation therapy (ADT) and docetaxel is a major challenge. Additionally, the ideal sequence of treatment remains unclear.⁴ Tolerability challenges with docetaxel have led some groups to study alternative, and potentially more tolerable, chemotherapy with cabazitaxel. “One study that I think we need to be thinking about is a study of ADT plus docetaxel versus ADT plus cabazitaxel, with everyone getting [novel hormonal therapy] background therapy,” said Christopher Sweeney, MBBS, of the Dana-Farber Cancer Institute. Noting the tolerability and adherence challenges, Dr. Sweeney said, “We struggle with getting people to use docetaxel, but could we get people to use cabazitaxel in the up-front setting?” Asking such questions is important for moving the field of prostate cancer management forward and for clarifying optimal patterns of care.

Advanced imaging modalities in prostate cancer have changed treatment paradigms and created uncertainties in management. As novel imaging enables identification of metastatic disease earlier than was previously possible, the population of patients with metastatic disease identified today is different from the population studied with treatments to manage metastases. These changes are concurrent with novel metastasis-directed therapies such as poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors and anti-prostate-specific membrane antigen (PSMA) therapies,^5,6 adding further complexity to the optimal sequencing of treatment.

Ongoing trials are underway and will hopefully provide clarity. According to Rana McKay, MD, a medical oncologist at the University of California, San Diego Moores Cancer Center, “There is a series right now of phase 3 trials that are currently ongoing in the metastatic hormone-sensitive space introducing PSMA-based therapy for PSMA-positive disease, PARP inhibition for biomarker-positive disease, AKT inhibition for people with PTEN loss, and also looking at CDK4/6 inhibition in this setting.” Commenting on the importance of these upcoming trial results, Dr. McKay noted, “They are likely to change the whole paradigm of what we do in mHSPC.”

Despite excitement about the forthcoming results, experts differ on the future of prostate cancer management. “In 2027, I think we are going to be dividing the disease of prostate cancer into synchronous and metachronous disease and into patients that we can treat with metastasis-directed therapy and the rest,” said Nick James, MBBS, PhD, FRCP, FRCR, of the Institute of Cancer Research, London. However, other experts are more optimistic about further development of biomarkers to inform management.

Daniel George, MD, of the Duke University School of Medicine, believes “the current therapies available today will be more prevalent in our practice in mHSPC populations, including novel androgen receptor-targeting therapies and docetaxel chemotherapy, but I think what is going to change is our assessment of frontline patients. We are going to be doing as a standard not just bone scans and [computed tomography] scans, but we are also going to be testing for PSMA and doing much more standard genetic testing—both germline and somatic.” De-escalation of therapy is also on the horizon. Neeraj Agarwal, MD, of the Huntsman Cancer Institute at the University of Utah, said “By 2027, the median survival of patients with mHSPC will approach 10 years, and we will be emphasizing de-escalation of therapy and maintaining quality of life for our patients.”

Renal Cell Carcinoma

The present management of renal cell carcinoma (RCC) in the frontline setting comprises multiple potential combinations, including single-agent immunotherapy, immunotherapy combinations, and targeted agents in combination with immunotherapy. However, most experts agree that ipilimumab in combination with nivolumab may be the most appropriate choice for most patients in the frontline setting.^7,8

Although results of the COSMIC-313 clinical trial evaluating cabozantinib plus ipilimumab/nivolumab showed positive results in improving progression-free survival in frontline disease, subgroup analyses showed that the benefits of therapy are concentrated in intermediate-risk patients, with little improvement in outcomes in poor-risk patients.⁹ As a result, some clinicians are unsure of how to incorporate a triple therapy regimen and continue to support doublet IO-based combination therapy as the standard of care. However, continued development is welcomed by oncologists.

Tian Zhang, MD, of the University of Texas Southwestern Medical Center, noted, “We have a great number of active immunotherapy-based combinations in RCC in the frontline setting approved for our patients.” With a wealth of options available, Dr. Zhang emphasized the importance of individualizing therapy for each patient. “Certainly, thinking about patient characteristics, and comorbidities, allows us to select the right approach,” she said.

Renal cell carcinoma management developments include advances in treatments targeting multiple novel pathways such as hypoxia-inducible factor-2 alpha (HIF-2α) and CD70 receptors.^10-13 David McDermott, MD, of the Beth Israel Deaconess Medical Center, expressed enthusiasm for HIF-2α targeting in particular. “The fact that we are seeing activity shows that HIF2 is an important target,” he said. Specifically, recent positive data indicate single-agent activity with the HIF-2α inhibitor belzutifan ranging from 25% to 31% across study arms, with response rates as high as 57% when used in combination with cabozantinib.^10,11

Regarding these results, Dr. McDermott noted, “Belzutifan has activity and a very favorable toxicity profile, but we are seeing activity in a subset of patients. The activity is delayed, but in the patients who benefit, it is often prolonged.” He encouraged a path of development that focuses on the patients most likely to benefit rather than the conventional approach of initiating therapy in the later-line settings and slowly moving to earlier-line settings. “Let’s identify those tumor markers to predict who will benefit and then move HIF inhibition up sooner. And there are other combinations we can use to build on this success for patients who are not likely to benefit from an immune checkpoint inhibition strategy.” Innovative clinical trial strategies focusing on biomarkers that predict which therapies are optimal for specific patient groups will inform optimal management of renal cell carcinoma in the future.

Conclusions

The Uromigos Live & Unplugged event provided a unique forum for integrating the perspectives of multiple global experts in a live format to inform both the current state and future of management across urologic malignancies. With multiple exciting developments incorporating novel mechanisms, biomarkers for selection of targeted therapy, and innovative treatment approaches, clinicians can look forward to continued progress in the management of patients with bladder cancer, prostate cancer, and renal cell carcinoma.

Through innovative, engaging, and entertaining live events such as The Uromigos Live & Unplugged, more clinicians can gain a clear understanding of both the state-of-the-art and future directions in care for the benefit of their patients. According to co-host Dr. Brian Rini, following the event, “We accomplished our goals and can build on this format moving forward to further innovate and change the face of medical education.”

Michael R. Page, PharmD, RPh is a medical director and medical communications consultant with Advantific, LLC. He earned his doctorate in pharmacy at the Ernest Mario School of Pharmacy at Rutgers University and is a registered pharmacist in New Jersey.

 

References

1. Bladder Cancer V2.2022. National Comprehensive Cancer Network. May 20, 2022. Accessed November 20, 2022. https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf
2. Rosenberg JE, Milowsky M, Ramamurthy C, et al. Study EV-103 cohort K: antitumor activity of enfortumab vedotin (EV) monotherapy or in combination with pembrolizumab (P) in previously untreated cisplatin-ineligible patients (pts) with locally advanced or metastatic urothelial cancer (la/mUC). OncologyPRO. September 12, 2022. Accessed November 20, 2022. https://oncologypro.esmo.org/meeting-resources/esmo-congress/study-ev-103-cohort-k-antitumor-activity-of-enfortumab-vedotin-ev-monotherapy-or-in-combination-with-pembrolizumab-p-in-previously-untreated-c
3. Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med. 2021;384(22):2102-2114. doi:10.1056/ NEJMoa2034442. Published correction appears in N Engl J Med. 2021;385(9):864.
4. Prostate Cancer V1.2023. National Comprehensive Cancer Network. September 16, 2022. Accessed November 20, 2022. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf
5. Sartor O, de Bono J, Chi KN, et al. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. 2021;385(12):1091-1103. doi:10.1056/NEJMoa2107322
6. Saad F, Armstrong AJ, Thiery-Vuillemin A, et al. PROpel: phase III trial of olaparib (ola) and abiraterone (abi) versus placebo (pbo) and abi as first-line (1L) therapy for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2022. doi: 10.1200/JCO.2022.40.6_suppl.011
7. Motzer RJ, Choueiri TK, McDermott DF, et al. Biomarker analysis from CheckMate 214: nivolumab plus ipilimumab versus sunitinib in renal cell carcinoma. J Immunother Cancer. 2022. doi:10.1136/jitc-2021-004316
8. Kidney Cancer V3.2023. National Comprehensive Cancer Network. September 22, 2022. Accessed November 20, 2022. https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf
9. Choueiri TK, Powles TB, Albiges L, et al. Phase III study of cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) in previously untreated advanced renal cell carcinoma (aRCC) of IMDC intermediate or poor risk (COSMIC-313). OncologyPRO. 2022. Accessed November 20, 2022. https://oncologypro.esmo.org/meeting-resources/esmo-congress/phase-iii-study-of-cabozantinib-c-in-combination-with-nivolumab-n-and-ipilimumab-i-in-previously-untreated-advanced-renal-cell-carcinoma-arc
10. Bauer TM, Choueiri TK, Papadopoulos KP, et al. The oral HIF-2 α inhibitor MK-6482 in patients with advanced clear cell renal cell carcinoma (RCC): updated follow-up of a phase I/II study. J Clin Oncol. 2022. doi:10.1200/JCO.2021.39.6_suppl.273
11. Choueiri TK, Bauer T, Merchan J, et al. Phase II study of belzutifan plus cabozantinib as first-line treatment of advanced renal cell carcinoma (RCC): cohort 1 of LITESPARK-003. OncologyPRO. 2022. Accessed October 24, 2022. https://oncologypro.esmo.org/meeting-resources/esmo-congress/phase-ii-study-of-belzutifan-plus-cabozantinib-as-first-line-treatment-of-advanced-renal-cell-carcinoma-rcc-cohort-1-of-litespark-003
12. CRISPR Therapeutics. CRISPR Therapeutics presents positive results from its phase 1 COBALT™-LYM trial of CTX130™ in relapsed or refractory t cell malignancies at the 2022 European Hematology Association (EHA) Congress. 2022. Accessed November 20, 2022. https://crisprtx.gcs-web.com/news-releases/news-release-details/crispr-therapeutics-presents-positive-results-its-phase-1
13. Flieswasser T, Van den Eynde A, Van Audenaerde J, et al. The CD70-CD27 axis in oncology: the new kids on the block. J Exp Clin Cancer Res. 2022;41(1):12. doi:10.1186/ s13046-021-02215-y