BY WALTER STADLER, MD, FACP
Fred C. Buffett Professor of Medicine and Surgery,
Chief, Section of Hematology/Oncology,
Director, Genitourinary Program
University of Chicago Medicine
The GU sessions at ASCO 2014 included one major practice-changing and several additional interesting and timely presentations. The obvious practice-changing study was the ECOG 3805 CHAARTED study of standard androgen ablation with or without docetaxel as initial therapy for patients with metastatic prostate cancer (Abstract LBA2).
This NCI-funded national cooperative inter-group trial was based on the hypothesis that these cancers include cellular clones that are less responsive to androgen receptor (AR) targeted therapy, but are sensitive to tubule-directed therapy, and rapidly emerge under the selective pressure of castration to cause the well-known clinical consequences of castration-resistant prostate cancer (CRPC). Notably, the trial had been somewhat controversial in the community with many so-called experts (including this author) predicting that it would not be able to show any difference. In a major triumph of the National Clinical Trials system and a tribute to the perseverance of the investigators, the trial was not only positive, but dramatically so.
Overall median survival in patients initially treated with combination therapy was 57.6 vs. 44.0 months in the control group, a hazard ratio of 0.61 that was statistically significant at the p<0.0003 level. Of note, the benefit appeared to be driven by patients with “high tumor burden,” which was defined a priori in the protocol, but in truth was a somewhat arbitrary distinction. Nevertheless, and as pointed out by the discussant Dr. Morris, it behooves the practicing community to apply these findings appropriately in patients similar to the study group, and should not be applied indiscriminately to all patients with castration-sensitive prostate cancer. While practice patterns and certainly some ongoing clinical trials will need to be modified on the basis of this new information, it is gratifying to recognize that these results provide additional support for the ongoing trial of androgen ablation plus docetaxel in the neoadjuvant setting for locally advanced disease (CALGB 90203).
While this plenary session presentation was clearly the most important, a number of additionally interesting prostate cancer studies were presented. Dr. Armstrong shared updated results from a study of the AR antagonist enzalutamide vs. placebo in pre-chemotherapy patients (PREVAIL) showing that there was both a progression-free as well as overall survival benefit (Abstract 5007). Secondary endpoints of time to chemotherapy, time to PSA progression, radiologic response, time to first skeletal event, and quality of life analyses all favored the enzalutamide arm as well. This follows an earlier presentation at GU ASCO and should support the full regulatory approval of this agent in this patient population.
Interestingly, a phase 3 study of the CYP17 androgen synthesis inhibitor orteronel in a similar population did not demonstrate any improvement in overall survival despite a statistically significant improvement in progression-free survival (Abstract 5008). It remains unclear whether the lack of improvement in survival in the orteronel study is due to post-progression crossover of the placebo patients to other potent AR targeted therapies or whether this is due to an intrinsic limitation of the agent.
With increasing use of potent AR targeted agents in prostate cancer, it is becoming important to begin to elucidate mechanisms of resistance, and two abstracts discussed early findings. In the poster discussion session, Dr. Small and his colleagues from the west coast Stand Up To Cancer group showed that both AR amplification and mutation is detected in patients clinically resistant to these agents (Abstract 5020), and in an oral session presented by Dr. Antonarakis (Abstract 5001), detection of an AR deletion mutant (AR-V7), which eliminates the ligand binding domain of the receptor, was demonstrated to correlate with resistance to both enzalutamide and abiraterone.
Finally, and perhaps not surprisingly, in a population-based study from the long running CapSURE database, Dr. Garcia-Albeniz demonstrated that there was no difference in overall or disease-specific survival for immediate vs. delayed androgen-deprivation therapy for patients who suffered from biochemical recurrence of their disease following a definitive local treatment (Abstract 5003). This should support the practice of active surveillance for some of these patients, especially elderly patients who are at risk for complications from androgen deprivation and whose overall survival from comorbid diseases may be limited.
Bladder and Renal Cancers
The most interesting data from the bladder and renal cancer presentations was the confirmation that both of these cancers are sensitive to immune checkpoint inhibitors.
A presentation by Powles showed that a PDL1 targeted agent led to an approximately 20% response in refractory bladder cancer (Abstract 4525). Although patients whose tumors express PDL1 have apparent higher response rates, the data do not support that this should be a selection marker for treatment decisions. Larger trials are eagerly awaited. Similar results were seen with single-agent PD1 pathway directed therapies in renal cancer.
Investigators also attempted to combine PD1 and CTLA4 inhibitors as well as the PD1 directed and VEGFR pathway inhibitors for renal cancer. Although higher response rates were noted, the toxicity of these combinations was significant.
The other potentially interesting piece of data presented in renal cancer was the potential for IL6 to act as both a prognostic as well as a predictive biomarker for patients treated with VEGF pathway directed agents. Further studies delineating whether this would be helpful in regards to selecting patients for perhaps VEGF pathway vs. PD1 pathway directed agents in the future are eagerly awaited.
A possible predictive marker for cisplatin-based chemotherapy in bladder cancer was presented by Dr. Rosenberg, who demonstrated that ERCC mutations are strongly correlated with response to neoadjuvant chemotherapy in patients with locally advanced invasive disease (Abstract 4510). If confirmed, this could perhaps provide improved selection of patients for this standard of care. This is especially notable since the most recent trial of adjuvant cisplatin-based chemotherapy vs. chemotherapy at the time of recurrence was presented by Dr. Sternberg (Abstract 4500). This European study had great difficulty accruing and only 284 of the planned 660 patients were enrolled. As might be expected with such an underpowered trial, an improvement in progression-free but not overall survival was demonstrated.
ASCO 2014 thus taught us that use of a relatively inexpensive generic tubulin-targeted (“classic chemotherapy”) agent early in the course of disease for metastatic prostate cancer is helpful, at least in a subset of patients, and PD1 pathway directed agents will likely emerge as a part of the therapeutic armamentarium for patients with kidney and bladder cancer, although, the exact patient population most likely to respond remains to be defined. Finally ongoing work on predictive and prognostic biomarkers is yielding some fruit, and further work and data in this area is eagerly awaited.