Ulka Nitin Vaishampayan, MBBS, director, the Phase I Program, Rogel Cancer Center, professor, internal medicine, University of Michigan, discusses patient factors to consider when choosing between apalutamide (Erleada), enzalutamide (Xtandi), and darolutamide (Nubeqa) for the treatment of patients with non-metastatic castration resistant prostate cancer (nmCRPC).

There are 3 FDA-approved regimens for the treatment of patients with nmCRPC: apalutamide, enzalutamide, and darolutamide, Vaishampayan begins. These 3 androgen receptor (AR) inhibitors were approved based on the phase 3 

, trials, respectively. All 3 clinical trials were similarly designed and were placebo controlled, double blinded, randomized trials with a primary end point of metastasis-free survival (MFS), she explains. Additionally, these trials used standard scans for imaging to determine the presence of metastases, Vaishampayan notes. Moreover, Vaishampayan adds that when considering using these therapies, she typically looks for patients with an adequate life expectancy who are healthy enough to tolerate AR inhibitors, keeping in mind any potential long-term comorbidities. A patient with no major competing comorbidities who has a long-term life expectancy is the kind of patient to select for this treatment, she adds.

It is also important to look at rapid doubling time, Vaishampayan expands. A prostate-specific antigen doubling time of 10 months or less was the threshold used in these studies, and patients receiving one of these 3 agents should have that doubling time as well, although other risk characteristics may also be important for patient selection, Vaishampayan says. Patients with small lymph nodes were also eligible for the studiesand should be considered for these therapies, Vaishampayan adds.

All 3 therapies have similar mechanisms of action with AR inhibition, though Vaishampayan says that she slightly leans toward treatment with darolutamide because of preclinical studies demonstrating the drug’s blood–brain barrier penetration. Patients with risk factors, such as seizures or [prior strokes], were allowed onto this agent’s study, whereas those patients were excluded from SPARTAN and PROSPER. However, all 3 agents have similar MFS outcomes, Vaishampayan emphasizes. Notably, further follow-up data have shown an overall survival benefit with darolutamide compared with placebo, Vaishampayan concludes.

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Ulka Nitin Vaishampayan, MBBS, discusses patient factors to consider when choosing between apalutamide, enzalutamide, and darolutamide for the treatment of patients with non-metastatic castration resistant prostate cancer.


Dr Vaishampayan on Patient Considerations When Choosing Between FDA-Approved Therapies in nmCRPC

Ulka Nitin Vaishampayan, MBBS, director, the Phase I Program at Rogel Cancer Center, professor of internal medicine, University of Michigan, discusses toxicities associated with various treatment options for patients with renal cell carcinoma (RCC).

Regarding TKIs, common adverse effects (AEs) typically include high blood pressure, diarrhea, and skin rash, Vaishampayan begins. Although these toxicities are common among anticancer therapies, they should be anticipated when anticipated when administering a TKI, and clinicians should have a strategy in place in preparation to manage these AEs, Vaishampayan says. She stresses the importance of informing the patient and their caregivers of monitoring for these toxicities. 

If these toxicities do occur, they need to be managed rapidly, Vaishampayan expands. Quick intervention allows for a greater likelihood for patients to remain on their respective therapies long term and potentially continue to derive benefit, she says.

However, patients who are frail could be more likely to experience significant toxicities, Vaishampayan says. When making treatment decisions for patients who are frail or have comorbidities, picking an agent such as axitinib (Inlyta) could allow for faster management and reversal of toxicities associated with this treatment, she explains. Agents such as lenvatinib (Lenvima) and cabozantinib (Cabometyx) have a longer half-life, which is something to consider when selecting treatment for this patient population, she adds.

Notably, dose adjustments of many treatments for RCC could help with the management of AEs, she explains, noting this is an option when toxicities begin to affect quality of life for patients or AEs recur.

One example of early toxicity management was seen with the regimen used in the phase 3 CheckMate 9ER (NCT03141177), which evaluated cabozantinib plus nivolumab (Opdivo), she says. The cabozantinib starting dose was reduced to 40 mg to help alleviate some of the toxicity that could be seen with this medication, Vaishampayan concludes. 

Ulka Nitin Vaishampayan, MBBS, discusses toxicities associated with various treatment options for patients with renal cell carcinoma.


Dr Vaishampayan on Toxicities Associated With Various Treatments in RCC

Ulka Nitin Vaishampayan, MBBS, director, Phase I Program, Rogel Cancer Center, Michigan Medicine, professor of internal medicine, University of Michigan, discusses the rationale of the phase 3 PROBE trial (NCT04510597) in advanced renal cell carcinoma (RCC).

The PROBE trial is an open-label study that will evaluate the efficacy of standard-of-care immunotherapy-based combinations with or without nephrectomy in patients with metastatic RCC. The PROBE trial is built on the phase 3 CARMENA trial (NCT00930033), which examined whether the addition of cytoreductive nephrectomy to standard treatment affects outcomes in patients with metastatic RCC, Vaishampayan explains. PROBE was designed because the treatment that was evaluated in CARMENA is no longer standard of care for metastatic kidney cancer, Vaishampayan adds.

The CARMENA trial examined treatment with sunitinib (Sutent) and showed that the addition of cytoreductive nephrectomy to sunitinib was noninferior to treatment with sunitinib alone, Vaishampayan continues. The PROBE trial is questioning whether cytoreductive nephrectomy will affect overall survival outcomes in a new treatment paradigm for metastatic kidney cancer, Vaishampayan concludes.

Ulka Nitin Vaishampayan, MBBS, discusses the rationale of the phase 3 PROBE trial in advanced renal cell carcinoma. 


Dr. Vaishampayan on the Rationale of the PROBE Trial in RCC 

Ulka Nitin Vaishampayan, MBBS, director, Phase I Program, Rogel Cancer Center, Michigan Medicine, professor of internal medicine, University of Michigan, discusses the design of the phase 3 PROBE trial (NCT04510597) in advanced renal cell carcinoma (RCC).

This randomized, open-label trial is evaluating the efficacy of standard-of-care immunotherapy-based combinations with or without nephrectomy in patients with advanced, metastatic RCC. All potential patients are treated with either 240 mg of intravenous (IV) nivolumab (opdivo) every 2 weeks, 480 mg of IV nivolumab every 4 weeks, 200 mg of IV pembrolizumab (Keytruda) every 3 weeks plus 5 mg of oral axitinib (Inlyta) twice per day, or 5 10 mg/kg of IV avelumab (Bavencio) every 2 weeks plus 5 mg of oral axitinib 5 mg oral twice per day. Patients are then randomized to receive nephrectomy or continue on treatment alone. Nephrectomies are conducted 8 weeks after randomization.

The primary endpoint of the trial is overall survival, and patients are stratified by ECOG performance status and risk level prior to randomization, Vaishampayan says. If patients are rapidly progressing while on any of the immunotherapy-based regimens, they are not considered eligible for the study, Vaishampayan explains.

Patients are required to have stable disease to be randomized and considered for nephrectomy. Randomization occurs between weeks 10 and 14 after the start of immunotherapy-based treatment, Vaishampayan concludes.

Ulka Nitin Vaishampayan, MBBS, discusses the design of the phase 3 PROBE trial in advanced renal cell carcinoma.


Dr. Vaishampayan on the Design of the PROBE Trial in RCC

Ulka Nitin Vaishampayan, MBBS, director, Phase I Program, Rogel Cancer Center, Michigan Medicine, professor of internal medicine, University of Michigan, discusses the utility of FGFR inhibitors in ​metastatic urothelial cancer.

FGFR inhibitors are a targeted therapy option for patients with metastatic urothelial cancer who harbor 

 fusions, Vaishampayan says. Erdafitinib (Balversa) is an FDA approved FGFR inhibitor that can be administered orally and has demonstrated significant efficacy in this patient population, Vaishampayan explains. 

Overall, it is essential to conduct next-generation sequencing earl​y to determine whether FGFR inhibitors are a therapeutic option for patients with newly diagnosed metastatic urothelial cancer, Vaishampayan concludes.

Ulka Nitin Vaishampayan, MBBS, discusses the utility of FGFR inhibitors in ​metastatic urothelial cancer. 


Dr. Vaishampayan on the Utility of FGFR Inhibitors in Urothelial Cancer 

Ulka Nitin Vaishampayan, MBBS, director, Phase I Program, Rogel Cancer Center, Michigan Medicine,professor of internal medicine, University of Michigan, discusses future directions for second-line treatment in urothelial cancer.

Beyond chemotherapy, several novel treatment options are available for the management of urothelial carcinoma, and it is important to profile tumors to inform available options, Vaishampayan explains. Moreover, as chemotherapy and immunotherapy are moving into earlier-line settings, some of the second-and third-line options will likely be moved earlier in the disease state, including the frontline setting, for patients with metastatic disease, Vaishampayan adds.

Antibody-drug conjugates (ADCs) have demonstrated remarkable efficacy in patients with advanced urothelial cancer, Vaishampayan continues. Currently, 2 ADCs are FDA approved, both utilizing distinct mechanisms of actions and associated with different safety profiles of non-overlapping toxicities, Vaishampayan concludes. 

Ulka Nitin Vaishampayan, MBBS, discusses future directions for second-line treatment in urothelial cancer. 

Dr. Vaishampayan on the Future Directions for Second-Line Treatment in Urothelial Cancer 

Ulka N. Vaishampayan, MBBS, FAB, director of the Phase I program at the Rogel Cancer Center and a professor of internal medicine at the University of Michigan, discusses the expanding role of TKI/immunotherapy combinations in metastatic renal cell carcinoma (mRCC). 

Several ​VEGF TKI/immunotherapy combinations have established efficacy in metastatic RCC, says Vaishampayan.

Inlyta) plus pembrolizumab (Keytruda) and axitinib plus avelumab (Bavencio) are approved for the treatment of patients with mRCC, says Vaishampayan. Both regimens have shown significant improvement​s in overall response rate (ORR) and progression-free survival (PFS) compared with sunitinib 

Additionally, findings from the phase 3 KEYNOTE-426 trial demonstrated an overall survival (OS) benefit with the combination of axitinib and pembrolizumab​.

Notably, results from the phase 3 CheckMate​-9ER trial, which were presented during the 

, demonstrated superiority with the combination of nivolumab (Opdivo) and cabozantinib (Cabometyx) ​vs sunitinib in terms of PFS, OS and ORR ​for the first-line treatment of patients with ​advanced RCC. 

In fact, the median PFS was doubled from 8​.3 months with sunitinib to 16.6 months with the combination, Vaishampayan concludes.

Ulka N. Vaishampayan, MBBS, FAB, discusses the expanding role of TKI/immunotherapy combinations in metastatic renal cell carcinoma. 

Dr. Vaishampayan on the Expanding Role of TKI/Immunotherapy Combinations in mRCC

Ulka N. Vaishampayan, MBBS, FAB, director of the Phase I program at the Rogel Cancer Center and a professor of internal medicine at the University of Michigan, discusses the safety profiles of tivozanib (Fotivda) versus sorafenib (Nexavar) in advanced renal cell carcinoma.

In terms of efficacy, tivozanib has shown to be superior in progression-free survival compared with sorafenib, says Vaishampayan. However, a statistically significant benefit in overall survival had not been observed with tivozanib over sorafenib. 

When choosing between the agents, the toxicity profiles of both agents have to be considered, as well as their mechanisms of action. Sorafenib has a RAF kinase inhibitor activity, as well as VEGF TKI activity, whereas tivozanib is a preferential VEGF TKI inhibitor only with selective activity against VEGF.

The toxicity profile of sorafenib seems to reflect a higher risk of hand-foot syndrome and skin rashes as compared with tivozanib. The risk of hypertension and other toxicities that are VEGF-related appear to be comparable between the agents, concludes Vaishampayan.

Ulka N. Vaishampayan, MBBS, FAB, discusses the safety of tivozanib versus sorafenib in advanced renal cell carcinoma.

Dr. Vaishampayan on the Safety of Tivozanib Versus Sorafenib in RCC

Ulka N. Vaishampayan, MBBS, FAB, director of the Phase I program at the Rogel Cancer Center and a professor of internal medicine at the University of Michigan, discusses the potential of tivozanib (Fotivda) in advanced renal cell carcinoma (RCC).

At present, tivozanib is not approved for use in the United States for patients with advanced RCC, although it has been approved in Europe; it is used as a single-agent VEGF TKI in this patient population, says Vaishampayan. In the United States, given the results of the phase 3 TIVO-3 trial, tivozanib could be a reasonable third-line option to consider for patients who have already received both VEGF TKI and immune-based regimens, adds Vaishampayan.

Tivozanib appears to prolong progressing-free survival, is relatively well-tolerated, and may provide patients with an additional efficacy benefit in the pretreated setting, concludes Vaishampayan.

Ulka N. Vaishampayan, MBBS, FAB, discusses the potential of tivozanib in advanced renal cell carcinoma.

Dr. Vaishampayan on the Potential of Tivozanib in Advanced RCC

Ulka N. Vaishampayan, MBBS, FAB, director of the Phase I program at the Rogel Cancer Center and a professor of internal medicine at the University of Michigan, discusses the need to develop novel therapies for patients with metastatic renal cell carcinoma (mRCC).

About 50% to 60% of patients with mRCC do not derive a response to immunotherapy or are considered refractory to immunotherapy, Vaishampayan says.

Although these patients may be salvaged with VEGF TKIs, the majority of patients are not being cured of their disease, explains Vaishampayan. 

As such, developing novel drugs and targets is critically important to continue moving the field of advanced RCC forward, concludes Vaishampayan.

Ulka N. Vaishampayan, MBBS, FAB, discusses the need to develop novel therapies for patients with metastatic renal cell carcinoma.



Dr. Vaishampayan on the Need to Develop Novel Therapies in mRCC 

Ulka N. Vaishampayan, MBBS, FAB, director of the Phase I program at the Rogel Cancer Center and a professor of internal medicine at the University of Michigan, discusses the benefit of axitinib (Inlyta) and pembrolizumab (Keytruda) in advanced renal cell carcinoma (RCC).

Updated results from the phase 3 KEYNOTE-426 trial showed that at 24 months of follow-up, patients who were given axitinib/pembrolizumab still experienced an improvement in survival, says Vaishampayan. The 2-year overall survival rate for patients who received sunitinib (Sutent) was 66% versus 74% of those who received the combination. The difference in benefit continues to be statistically significant, and as such, the immunotherapy-based regimen is still considered as the frontline therapy of choice for patients with RCC. adds Vaishampayan.

However, when looking at the International Metastatic RCC Database risk criteria, the favorable-risk subgroup did not show a benefit with axitinib/pembrolizumab; both arms experienced relatively similar outcomes. In the intermediate- and poor-risk subgroup, the difference remained and favored the axitinib/pembrolizumab regimen, concludes Vaishampayan.

Ulka N. Vaishampayan, MBBS, FAB, discusses the benefit of axitinib and pembrolizumab in advanced renal cell carcinoma.

Ulka N. Vaishampayan, MBBS, FAB

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