Pal Shares Insight on Abundance of Options in GU Malignancies

Sumanta Kumar Pal, MD

The field of genitourinary (GU) malignancies is seeing an influx of potential therapeutic options with a new drug application submitted for apalutamide (ARN-509) in prostate cancer, immunotherapy approvals in bladder cancer, and the promising results with frontline cabozantinib (Cabometyx) in kidney cancer.

In prostate cancer, Janssen Biotech recently announced the submission of a new drug application to the FDA for the next-generation oral androgen receptor inhibitor apalutamide for the treatment of patients with nonmetastatic castration-resistant disease.

In renal cell carcinoma (RCC), the primary analysis (investigator assessment) of the phase II CABOSUN trial showed a median progression-free survival of 8.2 months with the frontline use of cabozantinib compared with 5.6 months with standard sunitinib (Sutent) (HR, 0.66; 95% CI, 46%-95%; 1-sided P = .012). Based on these data, the FDA has granted a priority review to a supplemental new drug application for the frontline use of cabozantinib in RCC.

OncLive: Could you touch on some of the recent advances in GU cancers?

We saw exciting data at the 2017 ESMO Congress with cabozantinib. What kind of impact would this have if it is approved in the frontline setting for RCC?

Sumanta K. Pal, MD, recently chaired the OncLive^® State of the Science Summit^TM in Genitourinary Cancers and moderated a panel on kidney and bladder cancer options. In an interview during the meeting, Pal, a medical oncologist and assistant clinical professor in the Department of Medical Oncology and Therapeutics Research at City of Hope, discussed these advances and potential new therapies across GU malignancies.Pal: Across the board, there have been huge developments in each field. In bladder cancer, there have been a lot of developments in using immunotherapy, and our discussion today hinged on how these drugs are sequenced and how practitioners can choose between them. In kidney cancer, the big shockwaves came from CheckMate-214, a trial of nivolumab (Opdivo) and ipilimumab (Yervoy) in the frontline setting. Dr Neeraj Agarwal and others discussed how we could potentially incorporate that into our current therapy. Finally, we have a lot of discussion centered around prostate cancer, specifically the use of chemotherapy, and how to sequence radiation and local therapies—there were a lot of great topics across the board.There were a lot of new data from ESMO; I would definitely say that cabozantinib has proven itself as our best VEGF tyrosine kinase inhibitor (TKI) through CABOSUN. We see improvements in progression-free survival, response rate, and overall survival, and this has really stood up to the test of independent review. A lot of the data we saw there were confirmatory.

Will PD-L1 expression continue to play a role as a biomarker?

How can practitioners manage some of these side effects with the Immunotherapy combination?

Regarding prostate cancer, will we ever see a breakthrough with immunotherapy like we have seen with some of these other solid tumors?

When nivolumab and ipilimumab gets approved based on CheckMate-214, it is going to be hard to decide where to implement that regimen. Factors such as PD-L1 status may come to the forefront. We, for instance, do not see a lot of benefit with nivolumab and ipilimumab in the PD-L1—negative population—and that is 75% of patients. We also see that there are certain settings—for instance, non–clear cell disease—where a TKI may potentially be favored based on the data we have currently. There is going to be a big role for cabozantinib in many different settings, and clearly good-risk disease is one of those settings that we are going to have to focus on down the line. PD-L1 in kidney cancer is sort of a strange phenomenon. In the context of CheckMate-025, which looked at nivolumab versus everolimus (Afinitor), PD-L1 was really nothing but prognostic—it didn't really help predict therapies. However, in CheckMate-214, we really saw a different role for PD-L1 status, and the data point towards using PD-L1 as a selection criterion for patients who should receive a TKI versus nivolumab/ipilimumab. Outcomes were similar, but what I will say is that, with the nivolumab/ipilimumab strategy, we run into a lot of serious toxicities. Also, the financial cost is something that we need to be cognizant of in this healthcare climate.With nivolumab and ipilimumab, the side effect profile is so different than what we have become accustomed to with TKIs. With this regimen, we have to highlight the potential possibilities for severe immune-related toxicities. When patients come in with "typical" toxicities such as diarrhea or liver function test abnormalities, it’s a cue for us practitioners to treat those seriously and consider early implementation of steroids. Right now, in the context of prostate cancer, immunotherapy is relegated to those patients who have microsatellite instability—high disease or have hypermutated states, more or less. It’s hard for me to envision now that these drugs that we are using in the clinic—pembrolizumab (Keytruda), nivolumab—[will have] a role beyond [those patients].

Could you discuss apalutamide and its potential impact in prostate cancer?

Looking to the future, what do you think we are going to see in GU cancers?

Having said that, with combinations such as PARP inhibitors with these therapies, or perhaps second-generation strategies combining drugs, we may potentially "release the breaks" in the contexts of immunotherapy and get some great responses [in prostate cancer].There is really a role for drugs like apalutamide in the prostate cancer armamentarium, and what we see happening in prostate cancer is very similar to what has been happening in kidney cancer over the past decade, where we have VEGF TKIs and other agents that really supersede one another but have the same base mechanism of action. For instance, TAK-700 is a drug that Dr Neeraj Agarwal is championing through a SWOG trial, and that study has the same potential as apalutamide to change paradigms and [affect] how we treat advanced prostate cancer. Down the line, combinations are the way of the future. For instance, we have a trial at City of Hope looking at cabozantinib with atezolizumab (Tecentriq) in combination, and that takes the best of both worlds. This is because we have our most potent VEGF TKI in cabozantinib and paring that with an immune [checkpoint] inhibitor with atezolizumab. This is a trial that is going to be spanning bladder, prostate, and kidney cancer—and that is really exciting.

Choueiri TK, Hessel C, Halabi S, et al. Progression-free survival (PFS) by independent review and updated overall survival (OS) results from Alliance A031203 trial (CABOSUN): Cabozantinib versus sunitinib as initial targeted therapy doe patients (pts) with metastatic renal cell carcinoma (mRCC). In: Proceedings from the 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract LBA38.