Perspectives on the future of urothelial carcinoma therapy: chemotherapy and beyond

ABSTRACT

Introduction

Despite recent developments in the landscape of urothelial carcinoma (UC) treatment, platinum combination chemotherapy still remains a milestone. Recently immunotherapeutic agents have gained ever-growing attractivity, particularly in the metastatic setting. Novel chemotherapeutic strategies and agents, such as antibody-drug conjugates (ADCs), and powerful combination regimens have been developed to overcome the resistance of most UC to current therapies.

Areas covered

Herein, we review the current standard-of-care chemotherapy, the development of ADCs, the rationale for combining therapy regimens with chemotherapy in current trials, and future directions in UC management.

Expert opinion

Immunotherapy has prompted a revolution in the treatment paradigm of UC. However, only a few patients experience a long-term response when treated with single-agent immunotherapies. Combination treatments are necessary to bypass resistance mechanisms and broaden the clinical utility of current options. Current evidence supports the intensification of standard-of-care chemotherapy with maintenance immunotherapy. However, the optimal sequence, combination, and duration must be determined to achieve individual longevity with acceptable health-related quality of life. In that regard, ADCs appear as a promising alternative for single and combination strategies in UC, as they specifically target the tumor cells, thereby, theoretically improving treatment efficacy and avoiding extensive off-target toxicities.

KEYWORDS:

• antibody-drug conjugates
• bladder cancer
• chemotherapy
• combination therapy
• epigenetic modifiers
• immunoconjugates
• peptide-drug conjugates
• targeted therapy
• upper tract urothelial carcinoma
• urothelial carcinoma

Article highlights

• Platinum-based combination chemotherapy, especially cisplatin-based, remains the standard of care for first-line neoadjuvant systemic treatment for platinum-eligible non-metastatic muscle-invasive urothelial carcinoma (UC) patients. Even though it provides limited long-term benefits in metastatic settings and up to 50% of patients are considered cisplatin-ineligible or unfit, cisplatin-based chemotherapy remains the most efficacious chemotherapeutic for UC.

• The introduction of immune checkpoint inhibitors (ICIs) has revolutionized the treatment landscape of UC. However, only a few patients (20-30%) will be able to receive these agents and present durable clinical benefits, with progression and relapses occurring in most cases.

• Two antibody-drug conjugates (ADCs), enfortumab vedotin (EV) and sacituzumab govitecan (SG), show promising single agent results for salvage therapy in metastatic UC (mUC) patients after one or more prior lines of therapy.

• Several ongoing trials, including novel ICIs, ADCs, targeted therapies, and epigenetic modifiers show encouraging preliminary results alone or in combinations.

• Combination treatments are needed to overcome resistance and broaden the clinical utility of each agent by simultaneously or sequentially utilizing different modes of action and targeting complementary and parallel treatment pathways.

This box summarizes key points contained in the article.

Abbreviations

Ab, antibody; AC, adjuvant chemotherapy; ADCs, antibody-drug conjugates; AEs, adverse events; aUC, advanced urothelial carcinoma; BSC, best supportive care; CSS, cancer-specific survival; DC, dendritic cell; ddM-VAC, dose-dense M-VAC; DFS, disease-free survival; DV, disitamab vedotin; EGFR, epidermal growth factor receptor; EV, enfortumab vedotin; FdCyd, 5-fluoro-2’-deoxcytidine; FGFR, fibroblast growth factor receptor; GC, gemcitabine and cisplatin; HDACi, histone deacetylases inhibitors; HER2, human epidermal growth factor receptor 2; HMA, DNA hypomethylating agent; ICIs, immune checkpoint inhibitors; IMADCs, immune-modulating antibody-drug conjugates; ISACs, immune-stimulating antibody conjugates; ITT, intention to treat; M-VAC, Methotrexate, Vinblastine, Adriamycin, Cisplatin; mAb, monoclonal antibody; MDSCs, myeloid-derived suppressor cells; MIBC, muscle-invasive bladder cancer; MMAE, monomethyl auristatin E; mOS, median overall survival; mPFS, median progression-free survival; mUC, metastatic urothelial carcinoma; NAC, neoadjuvant chemotherapy; ORR, overall response rate; OS, overall survival; PARPi, poly (ADP-ribose) polymerase inhibitors; pCRR, pathologic complete response rates; PD-1, programmed cell death 1; PD-L1, programmed cell death-ligand 1; PDCs, peptide-drug conjugates; PFS, progression-free survival; RC, radical cystectomy; RKTs, receptor tyrosine-kinases; SG, sacituzumab govitecan; SN-38, 7-Ethyl-10-hydroxycamptothecin; SoC, standard of care; TD, trastuzumab duocarmazine; THU, tetrahydrouridine; TKIs, tyrosine-kinase inhibitors; TME, tumor microenvironment; TRAEs, treatment-related adverse events; Treg, regulatory T cells; TROP-2, trophoblast cell surface antigen 2; UC, urothelial carcinoma; UTUC, upper tract urothelial carcinoma; VEGFR, vascular endothelial growth factor receptor; WDR5, WD Repeat Domain 5

Authors’ contributions

Alberto Bianchi: project development, data research, and manuscript writing. Markus von Deimling, Maximilian Pallauf, Takafumi Yanagisawa, Tatsushi Kawada, Hadi Mostafaei, Fahad Quhal, Ekaterina Laukhtina, Pawel Rajwa, Muhammad Majdoub, Reza Sari Motlagh, Benjamin Pradere, Pierre I. Karakiewicz, Maria Angela Cerruto, Alessandro Antonelli: language and general revision. Shahrokh F. Shariat: supervision and critical revision.

Declaration of interest

SF Shariat has: honoraria from Astellas, AstraZeneca, BMS, Ferring, Ipsen, Janssen, MSD, Olympus, Pfizer, Roche, Takeda; a consulting or advisory role with Astellas, AstraZeneca, BMS, Ferring, Ipsen, Janssen, MSD, Olympus, Pfizer, Pierre Fabre, Roche, Takeda; and is in the speakers bureau for Astellas, AstraZeneca, Bayer, BMS, Ferring, Ipsen, Janssen, MSD, Olympus, Pfizer, Richard Wolf, Roche, Takeda. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.