Learning Objectives

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

• Describe the components of a multidisciplinary urologic cancer clinic and identify the best structure for the practice.
• Deliver advanced therapeutics based on current and emerging best evidence including immunotherapy in urologic oncology patients.
• Identify opportunities for shared care and team-based approaches of patients with urologic cancers including advanced prostate, bladder, and kidney cancer.
• Demonstrate an understanding of advances in genomic testing and personalized medicine for urologic cancers.
• Differentiate between new therapeutics that expand the treatment options for patients with urologic cancers and alter the definitions of cancer treatment.

The Multidisciplinary Oncology Clinic

The delivery of care for cancer patients has become increasingly complex given the pressures to see increasing numbers of patients, with mounting administrative burden and personalized treatment plans with new targeted therapies. The Multidisciplinary Oncology Clinic (MDC) is one way that urologists can work with other cancer care providers to create advanced multimodality treatment plans. Governing bodies and professional groups have identified multidisciplinary care as a marker for quality and improved outcomes.¹ In some countries, national guidelines have been established supporting the use of MDC teams to coordinate treatment of cancer patients.² However, even when required, utilization of MDCs remains low for urologists.³ For urologists, several MDC models have been proposed including all-in-one, where all providers meet a patient in the same clinic space, or virtual clinics where patients move from one member’s clinic to another.⁴ The COVID-19 pandemic has necessitated widespread and substantial changes in health care delivery, including the routine use of video visits, teleconsultations and other forms of electronic communication. Virtual MDCs are an attractive option that could potentially surmount the barriers to implementing single-location MDCs, such as patient travel time, transportation costs, access to transport, and physician time and space limitations

Multidisciplinary Approach to Prostate Cancer Care

The evolution of treatment for advanced prostate cancer was jumpstarted by the results of the CHARRTED trial for men with metastatic hormone-sensitive prostate cancer (mHSPC).⁵ The study found a significant improvement in the primary outcomes of overall survival in patients receiving docetaxel with androgen deprivation (ADT) compared to ADT alone. Importantly, in a followup to the study it was found that the benefit was specifically in the group of men with de novo and high-volume metastatic disease.⁶ This provides an opportunity for urologists to participate in MDC care for patients with high-volume disease at presentation. These findings were further supported by the STAMPEDE trial.⁷ The management of mHSPC with advanced androgen axis agents, such as abiraterone, apalutamide, and enzalutamide, is supported by the Latitude, TITAN and both the ENZAMET and ARCHES trials, respectively.^8–11 The results of these trials have increased the complexity of the treatment landscape for patients with advanced prostate cancer and provide another opportunity for urologists to integrate these therapies into their advanced prostate cancer practice. Radiation therapy to the primary represents another opportunity for MDC care in patients with mHSPC. The STAMPEDE trial evaluated radiation therapy in patients treated with docetaxel + ADT. For the entire population, there was no benefit to radiation to the primary, but when stratifying as low- vs high-volume disease, there was a significant improvement in survival in low volume patients who received radiation therapy to the primary.

Patients with nonmetastatic (M0), castration resistant prostate cancer (M0CRPC) are an important group of patients to consider given the worse overall survival with disease progression to metastasis. Treatment options now include the use of apalutamide,¹² enzalutamide¹³ and darolutamide,¹⁴ which have been shown to increase both time to metastasis and overall survival. Ideally treatment would be given at a low prostate specific antigen (PSA) doubling time (<10 months), providing another opportunity for multidisciplinary treatment coordination to ensure patients with M0CRPC receive systemic therapy more efficiently to prevent disease progression.

Patients with metastatic castration resistant prostate cancer (mCRPC) also provide an opportunity for MDC care. For patients with asymptomatic mCRPC treatment options traditionally include abiraterone, enzalutamide, sipuleucel-T and docetaxel.¹⁴ Fortunately, patients with mCRPC have several treatment options though optimal sequence of treatments has yet to be determined.

Sipuleucel-T is a patient-derived immunotherapy for patients who have no or minimal symptoms. This was found to improve overall survival without a PSA or radiographic response, especially in African American men. Both abiraterone and enzalutamide are oral agents that can be managed by either a medical oncologist or urologist. The inhibitory action of abiraterone on the cytochrome (CYP) enzymes may result in disturbances in potassium levels, edema, or liver enzyme elevations. Frequent monitoring at initiation is required and can be co-managed by an advanced practice provider familiar with the side effects of abiraterone. Docetaxel chemotherapy is also available as a first-line agent for mCRPC and may be preferred over other agents in patients with widespread or visceral metastases. For patients with symptomatic mCRPC, particularly for bone metastases in the absence of visceral metastases, radium-223 can be offered as a bone-seeking isotope that targets areas of bone metastases.

Genetic testing is recommended in patients with advanced prostate cancer with up to 30% of men with mCRPC harboring a deleterious DNA repair gene mutation.^15,16 Selective patients with deleterious germline or somatic mutations in 2 poly (ADP-ribose) polymerase (PARP) are eligible for directed therapies with PARP inhibitors (PARPi). The PARPi olaparib is approved for patients with mCRPC with a known PARP mutation who have progressed following androgen receptor directed therapy or taxane based chemotherapy.¹⁵ Likewise, patients with mCRPC found to have a BRCA1 or BRC2 gene mutation who have disease progression following traditional therapy are eligible for use of the PARPi rucaparib.¹⁷ PARPi use in both these populations is noted to significantly improve progression-free survival

Pembrolizumab has also been recently approved for those patients with microsatellite instability-high or mismatch repair-deficient mCRPC following docetaxel and targeted endocrine therapy with favorable progression-free and overall survival.^16,18 Given the new targeted therapies for patients with mCRPC incorporating genetics and genetic counselors will likely become an important component of MDC.

Multidisciplinary Kidney Cancer Treatment

Until recently, the primary role of surgical management for advanced kidney cancer was the removal of the primary tumor with the hope that patients do not have disease recurrence. However, many patients are at high risk for recurrence. Several agents have been tested as adjuvant therapies to prevent recurrence. Most of the studies of adjuvant therapy have been negative. Sunitinib is currently the sole adjuvant therapy with potential benefit in the adjuvant setting based on results of the S-TRAC study.¹⁹ The study showed an improvement in disease-free survival, but no improvement in overall survival in these patients. However, in the recent KEYNOTE-564, patients with locoregional clear cell renal cell carcinoma (RCC) with high risk of recurrence following nephrectomy were randomized to receive pembrolizumab vs placebo.²⁰ This cohort of patients included those patients with M1 disease with completely resected metastasis at or shortly following nephrectomy. In this study patients who received pembrolizumab experienced a significant improvement in disease-free survival following nephrectomy compared with placebo.

Although adjuvant therapy has not become widespread in high-risk kidney cancer, there are several areas where additional therapy in an MDC setting may be beneficial. Neoadjuvant therapy has been proposed to downstage tumors prior to surgical intervention. Recent reports have included preoperative pazopanib and axitinib, both of which can produce tumor shrinkage.^21,22 In a recent advancement patients with von-Hippel Lindau (VHL)-associated RCC are eligible for use of the HIF2a inhibitor, MK-6482 or belzutifan. This medication has been approved by the U.S. Food and Drug Administration (FDA) to slow tumor growth with significant improvements noted in tumor volume, treatment durations, relapse rates and progression-free survival.²³

The expansion of treatment options for metastatic kidney cancer has resulted in a re-evaluation of the benefit of cytoreductive nephrectomy. The CARMENA trial evaluated treatment-naïve patients with biopsy proven metastatic clear cell renal cell carcinoma randomized to sunitinib alone vs cytoreductive nephrectomy plus sunitinib in a non-inferiority study.²⁴ The study showed that sunitinib alone was not inferior to cytoreductive nephrectomy followed by sunitinib. However, the study was enriched with patients at high risk who may have been poor surgical candidates. The results suggest that a nuanced approach to patients with metastatic kidney cancer may be most beneficial. Several next generation cytoreductive nephrectomy and radiation trials are ongoing.

Multidisciplinary Bladder Cancer Treatment

There are several opportunities for multidisciplinary care within the realm of bladder cancer. Bacillus Calmette–Guérin (BCG)-unresponsive high-risk non-muscle-invasive bladder cancer (NMIBC) patients who decline or are ineligible for radical cystectomy are an especially challenging population. Treatment with the immunotherapeutic pembrolizumab is FDA approved for use in this population based on the KEYNOTE-057 trial with a 41% complete response rate and a median duration of complete response of 16.2 months.²⁵

Additionally, ongoing phase II trials investigating atezolizumab, a similar immuno-oncologic to pembrolizumab, in this patient cohort have reported encouraging complete responses at 3 and 6 months.²⁶ A novel intravesical gene-mediated therapy, adstiladrin, is also currently being investigated in this patient cohort with noted durable high-grade free recurrences up to 12 months.²⁷ With the advancement in both systemic and surgical treatments of NMIBC, multidisciplinary care is key to treatment of this population.

The benefits of multidisciplinary management including neoadjuvant chemotherapy prior to radical cystectomy and the importance of surgical quality as measured by lymph node count were shown in the SWOG 8710 trial.²⁸ A followup meta-analysis provided evidence of a 5% overall survival benefit at 5 years with neoadjuvant chemotherapy.²⁹ These findings support the recommendation in the AUA guidelines for an MDC approach to the patient with muscle-invasive bladder cancer.³⁰ For patients with metastatic disease, the cisplatin-based chemotherapy remains the first-line therapy of choice. However, immunotherapy including pembrolizumab and other PD-1/PD-L1 agents has recently been approved for second-line and cisplatin ineligible patients.

Conclusion

As advanced therapeutics become a growing part of the management of urological cancer patients, the urologist will be required to coordinate care among a growing number of oncology specialists. The creation of an MDC can provide the infrastructure to manage these patients along with the growing demands of clinical practice.