As in years past, ASCO 2017 provided important new, as well as confirmatory, information on the care of patients with genitourinary cancers and demonstrated the remarkable progress that has been made. We learned about the value of early potent androgen receptor targeting in prostate cancer, confirmed the value of immunotherapy in both bladder and renal cancer, and learned that germline mutations are not just important in breast, ovarian, and colon cancer patients.
Two of the most important studies for the entire meeting were on prostate cancer therapy. The choice of which abstract to present at the plenary session was surely a difficult one for the scientific program committee, since I would argue both were worthy (and in fact both were published in the same issue of the New England Journal of Medicine on the day of presentation), but I'm sure my colleagues focused on other important cancers might disagree.
Prostate Cancer Studies
In one study, Karim Fizazi MD, PhD, Head of the Department of Cancer Medicine at Gustave Roussy, University Paris-Sud in Villejuif, France, presented data from the LATITUDE study conducted by an international consortium of sites. She noted that the addition of abiraterone to standard androgen ablation in patients with castration-sensitive metastatic disease provided a dramatic overall survival benefit over castration therapy alone.
In the second presentation, Nicholas D. James, MBBS, PhD, FRCR, FRCP, Professor of Clinical Oncology at the University of Birmingham and Consultant Clinical Oncologist at Queen Elizabeth Hospital, Birmingham, U.K., presented data from the multi-arm STAMPEDE Trial from the British MRC demonstrating a similar highly dramatic survival benefit in castration-sensitive patients treated with androgen ablation plus abiraterone. Notably, in this trial, almost 50 percent of the patients had high-risk locally advanced or lymph node-positive disease and 41 percent also received definitive local radiotherapy.
The obvious question generated by these data is the relative advantage of additional abiraterone versus docetaxel, which has already become a standard of care for castration-sensitive metastatic patients. The prior STAMPEDE and CHAARTED data suggest that the benefit for chemotherapy is most notable in patients with high-volume metastatic disease defined somewhat arbitrarily as visceral disease and greater than four bone metastases, but this observation is largely due to the more limited number of patients with lower burden disease in the chemotherapy trials. The benefit of abiraterone, at least in this early analysis, appears to be more evenly distributed across prognostic groups, including patients with locally advanced disease.
In the discussion for the LATITUDE trial, Small pointed out that the relative survival advantage of chemotherapy and abiraterone was quite similar. While some might jump to the conclusion that docetaxel is more toxic, and thus not preferred, it behooves us to recognize that docetaxel is administered for a defined 18 weeks, whereas abiraterone is administered until progression, or up to 2 years in locally advanced patients.
Other obvious questions are whether both docetaxel and abiraterone together could provide an even greater survival advantage, whether even more intensive androgen receptor targeted therapy with an androgen synthesis inhibitor plus an androgen receptor antagonist is useful, and whether any of these observations also apply to patients with lower-risk disease such as biochemical recurrence only following definitive local therapy. All of these are the subject of ongoing research. It is remarkable that, more than 7 decades after the discovery that prostate cancer is an androgen-driven cancer, we continue to make important discoveries on how to manipulate this pathway for clinical benefit.
Renal Cancer Findings
In regards to renal cancer, a number of presentations demonstrated that various PD1 pathway-directed immunotherapies are highly-effective. We are now well into investigating obvious combination therapies, especially with the VEGF pathway-directed drugs, but the best combinations and sequences of therapy remain to be determined.
For example, combinations of avelumab plus axitinib appear promising but in a small clinical trial, whereas the combination of atezolizumab and bevacizumab was perhaps not as promising as hoped; although, certain immune-based biomarkers show promise as providing information for patient selection. The ongoing large phase III trials will be necessary to provide clinical guidance. It is, however, notable that there was also data on combination therapies that should not be pursued further insomuch as the combination of pazopanib and pembrolizumab led to intolerable hepatic toxicity. Another important negative trial was the phase III study of adjuvant pazopanib in locally advanced renal cancer, which in the context of data from other adjuvant trials suggests that surveillance remains the standard of care for this disease state.
Bladder Cancer Research
In bladder cancer, there is likewise maturing data regarding the role of PD1 pathway-directed immunotherapy. Perhaps the most important was presentation of the mature survival data from the pembrolizumab versus standard chemotherapy trial in patients with refractory urothelial cancer in which a survival benefit with pembrolizumab was clearly demonstrated, making this the primary choice for these patients, at least until other level one data is presented.
Genetic Updates
Finally, increasing data on the role of germline mutations in genitourinary malignancies was discussed. Specifically, somatic DNA repair mutations, most commonly BRCA2 mutations, were once again demonstrated to be present in ~25 percent of patients with advanced prostate cancer. These patients, as has been demonstrated previously, will respond to PARP inhibitors, but may also respond to platinum-based therapy. The relative value of these treatments, the role of these alterations in predicting response to androgen receptor targeted therapy, the role of germline versus somatic genomic testing, and the importance of tissue-based versus circulating DNA will keep researchers busy for several years and practitioners challenged as to how best to implement these findings into daily practice. What is clear at this point is that germline testing should clearly be done far more frequently in prostate cancer patients. This is surprisingly also relevant in urothelial cancer where Carlo and colleagues demonstrated that germline mutations, especially in the Lynch syndrome associate and DNA damage response genes, were present in 22 percent of all and in 29 percent of upper tract urothelial cancers.
WALTER STADLER, MD, FACP, is the Fred C. Buffett Professor of Medicine & Surgery and Section Chief of Hematology/Oncology at the University of Chicago.