Next-Generation Genitourinary Oncology: Keeping One’s Powder Dry

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The critical issue is that we need to be more cognizant of the value proposition than in past eras, and genitourinary oncologists must come to grips with the idea that finances for health care are becoming much more restricted.
— Derek Raghavan MD, PhD, FACP, FRACP, FASCO

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There is a new yin-yang of management in genitourinary oncology, with the balance of opposing power focused among cancer cells, kinase inhibition, and lymphocyte function, representing a shift in the fashions of treatment somewhat away from chemotherapy. This linear progress has been complicated by the litany of rules and regulations surrounding the Medicare Access and CHIP Reauthorization Act; the Merit-Based Incentive Payment System; a new reverence for big data; Republican plans for reconstruction, replacement, and/or repeal of the Affordable Care Act; as well as the crucially important increasing focus on value—all of which may make the application of our scientific progress more difficult.

Kidney Cancer

In the past decade, we have made important progress in the management of cancers of the prostate, bladder, and kidneys. The harbinger was the management of renal carcinoma, building on an increased understanding of the biologic impact of kinome function on the growth of clear cell carcinoma and an improved appreciation of the multifunctionality of molecular interactions in the growth and inhibition of this tumor.

Recent findings suggest the c-MET and vascular endothelial growth factor receptor inhibitor cabozantinib ­(Cabometyx) is active after failure of the more conventional tyrosine kinase inhibitors and may be more active than sunitinib (Sutent) in the front line. Further, researchers have recognized the importance of the interface between programmed cell death protein 1 (PD-1) and its ligand (PD-L1), with T-cell function as a non–cross-resistant mechanism to inhibit the growth of kidney cancer, representing a potentially easier (but possibly more expensive) option compared to interleukin-2 (Proleukin).

Bladder Cancer

Subsequently, the U.S. Food and Drug Administration (FDA) also blessed the PD-1/PD-L1 interface as a meaningful target for clinically relevant intervention in advanced bladder cancer. This should not be a surprise, as decades of work have shown that immunomodulation of noninvasive bladder cancer by bacillus Calmette-Guérin and interferon leads to sustained tumor regression.

The shibboleth that immunotherapy had no role in urothelial cancer was probably based on inadequate cancer trials, and more recent studies have clearly shown sustained anticancer efficacy of T-cell activators against advanced disease. Ongoing work will perhaps show that kinase inhibition, if appropriately focused by molecular target identification, also results in sustained tumor regression of bladder cancer—although it is important to note that the early use of sunitinib and similar agents in this setting did not have a clinically sustained outcome.

Prostate Cancer

Presentations at the 2016 ASCO Annual Meeting and the more recent Genitourinary Cancers Symposium demonstrated our growing knowledge of androgen receptor function and its implications for the clonal heterogeneity of prostate cancer. New-generation second-line hormonal agents (eg, abiraterone [Zytiga], enzalutamide [Xtandi]) reflect these new biologic constructs; they are active in this setting, and their clinical indications seem to be expanding. However, it is not yet beyond question that they should always replace less expensive drugs like ketoconazole.

New cytotoxic agents such as cabazitaxel (Jevtana) have shown activity in prostate cancer after the failure of initial docetaxel. However, this past year’s ASCO Annual Meeting had a heavy focus on value in the key prostate cancer session; as a result, it appeared that a lower dose (20 mg/m2) of cabazitaxel is less expensive and equally effective as the FDA-approved standard (25 mg/m2), that there is no indication to replace the less costly docetaxel with cabazitaxel in the first-line setting, and that there is no clear role for adjuvant cytotoxic treatment at present. Although immunotherapeutics took an initial hit in prostate cancer with some of the early, expensive options, renewed interest in leveraging PD-1 and T-cell targeting has opened this option to further testing.

The apparent lack of anticancer efficacy of kinome inhibition and related approaches against prostate cancer remains something of a mystery to me. The early-phase data for cabozantinib and the reduction of prostate cancer osseous metastases were encouraging, and it was a surprise when the randomized trial against prednisone was negative. Perhaps a greater precision in molecular mapping of resistant tumors may resolve this confusing situation.

Cost Issues

So here is the paradox: We have a batch of new therapies, most of which provide real tumor reduction with extension of time and improved quality of life. However, they are horrendously expensive at a time when the general population (especially those without friends/family who are cancer sufferers) is rapidly losing the appetite for expensive quality-of-life modulation or only modest time extension. It seems that the payers will increasingly govern treatment selection, and it will behoove us to lift our game, to focus on meaningful outcome improvements (measured in months to years rather than hours to days, or significant reductions in major toxicities).

It seems the hybrid academic–community cancer center model is gaining traction and making cancer trials more widely accessible. Given that molecular prognostication and targeted-agent utilization studies (eg, the ASCO TAPUR trial) are associated with the provision of free targeted agents, this will be a short-term mechanism for reducing the cost of care for patients who wish to participate in these studies. Given the proliferation of novel agents, I anticipate that the pharmaceutical industry will be happy to provide new drugs for testing in well-structured studies that accrue in a timely fashion, hoping in turn to gain market dominance.

If we set targets of improved outcome that are meaningful to the public at large, the genitourinary oncology community might take the lead in balancing the value proposition against general expectations. In renal carcinoma, it seems likely that the focus will shift to the assessment of adjuvant targeted therapies and improved molecular prognostication. In bladder cancer, we can expect greater use of PD-L1–active agents and maybe refinement in the blockade of tyrosine kinases and related proteins.

For prostate cancer, a greater understanding of the heterogeneity of androgen receptor function and associated genomic variation will lead to more accurate use of hormone therapies and better recognition of the emergence of hormonal resistance. In addition, there will probably be continued efforts to identify the optimal timing and selection of cytotoxic therapies, offset by careful cost accounting of a true associated community benefit.

Setting Priorities

The critical issue is that we need to be more cognizant of the value proposition than in past eras, and genitourinary oncologists must come to grips with the idea that finances for health care are becoming much more restricted. We must prioritize the following objectives:

  • Develop more rational use of expensive agents, setting clinical targets that are more meaningful than P values, highly selective waterfall plots, and small increments of progression-free survival.
  • Abandon the misuse of big data sets, which are often prey to heavy case selection bias, to support innovative treatment strategies for the population at large without securing robust level 1 supporting evidence.
  • Complete some conceptually dull but pragmatically important studies to validate the role of exciting new agents in direct comparison with less expensive and less interesting established treatments.
  • Develop mechanisms to allow greater participation of all segments of the population in cancer trials, including the removal of barriers to access.

If we adopt this stance, we should be able to keep our powder dry (viz, operate effectively with diminishing resources) and maintain a trajectory afforded by the molecular revolution. ■

Disclosure: Dr. Raghavan reported no potential conflicts of interest.