Learning Objectives

At the conclusion of the activity, participants will be able to:

• Describe the standard of care chemotherapy regimens for genitourinary malignancies.
• Recall both historic and newer immunotherapy options in the treatment of genitourinary malignancies, including recently approved checkpoint inhibitors and antibody-drug conjugates.
• Outline the mechanism of action of common chemotherapy and immunotherapy regimens for genitourinary malignancies.
• Recognize and manage the adverse events related to these agents and the survivorship issues surrounding patients on systemic treatments for genitourinary malignancies.
• List both completed and accruing clinical trials that are defining the paradigms of chemotherapy and immunotherapy use in genitourinary malignancies.

The next generation of management of advanced genitourinary malignancies is marked by multidisciplinary care, interdisciplinary conferences and collaborative efforts. Long gone are the days when these patients were treated by clinicians operating out of separate silos with outcomes often determined by 1 person making the majority of the decisions surrounding care. Often, these patients are starting in a urology office before they are referred for management of advanced or metastatic disease. In order to stay relevant and to maintain a relationship with the patient, urologists must be familiar with the newest agents and guidelines, including specific indications and side effects. This is our fourth consecutive year teaching this course, and in looking back at prior years it is very evident how rapidly the landscape for the treatment of advanced and metastatic prostate, bladder and kidney cancer has changed.

In advanced and metastatic prostate cancer, the arrival of the newest generation of androgen receptor-directed therapies and chemotherapy regimens have had the greatest impact. For metastatic castrate-sensitive disease (mCRPC), the newest guidelines include androgen receptor blockers enzalutamide and apalutamide, cytochrome P450 17 alpha-hydroxylase (CYP-17) inhibitor abiraterone, and docetaxel (which up to recently had been reserved for end-of-the-line castrate resistant prostate cancer (CRPC). In the next disease space, nonmetastatic CRPC, add darolutamide to these agents in addition to what had prior been standard of care. Finally, the largest changes in the last decade have been appreciated in the mCRPC disease space. Not only are the aforementioned androgen receptor-directed therapies represented in the guidelines, but also a new chemotherapy, cabazitaxel, and the bone-only metastasis agent radium-223.

For mCRPC, the impact of individualization of therapy and genomic analysis of tumors has been realized with regard to patients with homologous recombination repair gene-mutated disease, in which the poly-ADP ribose polymerase (PARP) inhibitors rucaparib and olaparib are selectively effective. Also in patients with mutations in mismatch repair genes (MMR) and/or microsatellite instability (MSI) in the tumor, the checkpoint inhibitor pembrolizumab has shown benefit, as in patients with other tumor types and these somatic gene mutations. As of now, the only other immunotherapy currently U.S. Food and Drug Administration (FDA)-approved for prostate cancer remains sipuleucel-T, which is used in nonvisceral, asymptomatic or minimally symptomatic M1 castration resistant disease. The labor-intensive mechanism of administration of sipuleucel-T and the lack of a reliable surrogate marker for treatment efficacy has limited its use in many outpatient settings, particularly that of the urologic oncologist.

There have now been 2 Consensus Conferences investigating the role of genetic testing for inherited prostate cancer risk, both taking place in Philadelphia. When reviewing the available literature, it has been determined that in germline testing of men with metastatic prostate cancer, up to 11.8% harbor a mutation compared to 4.6% of patients with localized disease. Over 20 mutations in DNA-repair genes have been identified, with the most common being BRCA2, BRCA1, ATM and CHEK2. Additionally, a consensus recommendation of the conference was to test all men with mCRPC, regardless of family history, to help identify any actionable mutations.¹

When considering advanced and metastatic urothelial carcinoma of the bladder, cisplatin-based chemotherapy remains the gold standard. However, up to 50% of eligible patients are deemed unfit for cisplatin administration because of poor functional status, chronic kidney disease, hearing loss, neuropathy or heart failure. Up until recently, these patients would either receive suboptimal chemotherapy regimens or no systemic therapy at all, which would severely diminish survival. This has been reversed with the discovery of new immunotherapeutic agents. Although the concept of immunotherapy for bladder cancer is not new, with bacillus Calmette-Guérin being a mainstay of treatment for noninvasive, high-grade urothelial carcinoma of the bladder, the recent excitement surrounding immunotherapy and bladder cancer lies in the introduction of the checkpoint inhibitors (CPIs) for the treatment of a variety of disease states. The astounding efficacy of this class of medications against urothelial cancer prompted a well-known and established genitourinary oncologist to state at an international meeting that he had “not seen such dramatic responses in my 30 years of treating these cancers.”

The checkpoint proteins are molecules that impede immune function (namely T-cell immunity). In a normal individual this immune regulation helps the body recognize self and prevent autoimmunity and immune overactivity. However, malignant cells can hijack this mechanism and mimic the signals released by healthy cells. In so doing, the immune system remains inactive against the malignant cells, allowing them to grow and proliferate unregulated. A CPI takes the proverbial foot off of the brake and activates the cellular response, allowing the immune system to attack the malignant cells.

The 3 checkpoint targets PD-1 and CTLA-4 (on the T-cell) and PD-L1 (on the tumor cell) are currently the focus of investigation. Pembrolizumab is a humanized monoclonal antibody against PD-1 that was studied in KEYNOTE-045, a large open label, international, phase III trial evaluating its efficacy in the platinum refractory setting. The positive results of this trial led to FDA approval of pembrolizumab for platinum refractory advanced urothelial carcinoma of the bladder. Additional CPIs that are FDA approved in this disease space are nivolumab (anti PD-1) and avelumab (anti PD-L1). The ORR for these agents range from 15%–25%, with a higher response in PD-L1 expressing tumors. Furthermore, atezolizumab (anti-PD-L1) and pembrolizumab have gained approval in the first line cisplatin-ineligible population. Also very exciting in the second line post platinum space is a biomarker-driven therapy involving erdafitinib for patients with an FGFR3 or FGFR2 alteration. In the post CPI space, second line and beyond, there is erdafitinib and the antibody-drug conjugates enfortumab and sacituzamab, which have shown significant activity in patients with advanced bladder cancer who have failed CPIs.

Two other areas in which CPIs have entered the guidelines for urothelial carcinoma of the bladder include bacillus Calmette-Guérin-unresponsive noninvasive, high-grade urothelial carcinoma of the bladder, in which pembrolizumab recently gained approval via the Keynote-057 trail; and, as maintenance therapy in patients with advanced or metastatic disease pretreated with chemotherapy, in which avelumab improved overall survival via the JAVELIN trial.

Like bladder cancer, renal cell carcinoma (RCC) is not a stranger to immunotherapy, particularly for the treatment of metastatic disease. From the 1990s to the early 2000s the only agents considered effective for patients with advanced RCC were high-dose interleukin-2 and interferon. In fact, much of the data concerning cytoreductive nephrectomy were based on patients receiving adjuvant interferon. However, harsh toxicities and relatively poor response rates associated with these older immunotherapy agents in part led to the quick conversion to the targeted therapy era in advanced RCC. These medications (eg sunitinib) were considered standard of care for approximately 10 to 15 years.

With the arrival of the CPIs came a new immunotherapy era for RCC, and new treatment paradigms. CheckMate-214 results were published in 2018 and demonstrated improved overall survival in the intermediate to poor risk metastatic clear cell RCC (ccRCC) cohort treated with ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) combination vs sunitinib monotherapy. Additionally, the combination CPI regimen was better tolerated. These results led to FDA approval of this regimen as first line treatment for intermediate to poor risk metastatic ccRCC. The KEYNOTE-426 trial evaluated a novel combination regimen of a CPI and targeted agent (pembrolizumab plus axitinib) for first line treatment of advanced ccRCC. This trial demonstrated a survival advantage regardless of risk stratification and led to the approval of this combination in all risk categories. Through the CheckMate-9ER trial, the combination of cabozatinib and nivolumab gained similar approval, again regardless of risk category. However, this regimen was also indicated for tumors of clear-cell histology. For those patients with advanced or metastatic non-ccRCC, the only preferred regimens remain sunitinib or an available clinical trial.

The new era of treatment for advanced and metastatic prostate, bladder and kidney cancer has been marked by genetic and genomic testing, biomarker-driven therapies, and the continued infiltration of several disease spaces by immunooncologic therapies. Annual review of the newest trials and approvals is absolutely necessary for the urologic oncologist and advanced practice providers alike to stay current.