2014 was a year of surprises in genitourinary cancer research. In prostate cancer, an unexpected, practice-changing result was reported for the CHAARTED trial in newly metastatic, hormone-sensitive prostate cancer: a marked survival benefit with docetaxel chemotherapy. In addition, overall survival data from PREVAIL demonstrated that enzalutamide has significant efficacy prior to chemotherapy in metastatic castration-resistant prostate cancer (mCRPC), leading to a new labeled indication. Furthermore, a molecular biomarker, AR-V7, demonstrated an intriguing ability to predict responsiveness to androgen signaling inhibitors in patients with mCRPC.
Finally, in bladder cancer, surprising clinical responses in a Phase I trial of the anti-PD-L1 therapy MPDL3280A have generated excitement around immunotherapy in a notoriously treatment-resistant cancer.
CHAARTED Sets New Course for Metastatic Hormone-Sensitive Prostate Cancer
At the Plenary Session of ASCO 2014, Sweeney et al presented potentially practice-changing results for the CHAARTED Study (ChemoHormonal Therapy vs. Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer), a randomized Phase III trial sponsored by the NCI and led by ECOG (Sweeney C et al. J Clin Oncol 32:5s, 2014 suppl; abstr LBA2).
In this trial, 790 men with newly diagnosed, metastatic hormone-sensitive prostate cancer were randomized either to primary androgen-deprivation therapy (ADT) or ADT plus six cycles of docetaxel chemotherapy (75 mg/m2 every 3 weeks). No daily prednisone was used.
Overall survival was significantly better in the docetaxel arm (57.6 vs. 44.0 months; HR 0.61, p=0.0003). In a subset analysis, patients with high-volume metastatic disease (defined as visceral disease and/or ≥ 4 bone metastases) had an even greater benefit from docetaxel, translating into a median survival benefit of 17 months (49.2 vs. 32.2 months; HR 0.60, p=0.0006). In patients with lower-volume disease, there was not yet a significant improvement in overall survival, although a trend towards improved survival was seen.
So is CHAARTED a game changer? Certainly for patients with high-volume metastatic hormone-sensitive disease, docetaxel should be offered. One perspective to frame the benefit of earlier chemotherapy is that the absolute median survival benefit of docetaxel in mCRPC is less than three months (in TAX327 compared with mitoxantrone) while in CHAARTED, the absolute difference in median survival was nearly 14 months.
There are risks to chemotherapy, however, so the risk-benefit ratio must be addressed. The European STAMPEDE trial will address a similar question and should be reported in 2015.
Is There an Optimal Sequence of Treatment for Metastatic Castration-Resistant Prostate Cancer?
Over the past several years, there has been an unprecedented run of new drug approvals in prostate cancer.
The drugs are also notable for their unique mechanisms of action—from immunotherapy to cytotoxic chemotherapy to androgen signaling inhibition to bone targeting. This streak was extended in 2014 with a new indication for the androgen signaling inhibitor enzalutamide in pre-chemotherapy mCRPC patients. Notably, these drug approvals occurred in a relatively short window of time with comparator arms that were either placebos or agents that do not improve survival.
As a result, a key issue in mCRPC moving forward is how to best sequence this relative “bonanza” of drugs for any given patient.
Enzalutamide was first approved in mCRPC patients who had already progressed after docetaxel chemotherapy. PREVAIL was a Phase III, randomized, placebo-controlled trial of 1,717 mCRPC patients who had not yet received docetaxel chemotherapy (Beer T, et al. N Engl J Med 2014; 371:424-433). The hazard ratio for overall survival was 0.71 (95% C.I. 0.60-0.84, p<0.001).
The other co-primary endpoint was radiographic progression-free survival and strongly favored the enzalutamide arm (HR 0.19; p<0.001). Enzalutamide was well-tolerated, with fatigue and hypertension the most common toxicities. Seizures were not reported, a concern from earlier trials. As a result of the PREVAIL trial, the FDA approved the use of enzalutamide in mCRPC for all patients whether they received docetaxel or not.
So should enzalutamide be used prior to docetaxel? Interestingly, a secondary endpoint in PREVAIL was to evaluate the median time to chemotherapy use, which was significantly longer in the enzalutamide arm compared with placebo (28 vs. 10.8 months, p<0.001).
In general, it is not hard to see why patients would prefer a relatively tolerable oral therapy compared with intravenous chemotherapy, especially as most of these patients were asymptomatic. For most patients, an oral androgen signaling therapy such as enzalutamide should be used before chemotherapy and indeed could delay chemotherapy use by nearly 18 additional months.
A Predictive Biomarker in mCRPC: Is AR-V7 a Breakthrough?
One downside of having multiple therapeutic options in mCRPC is a lack of guidance in deciding which to choose. Specifically, no clinical, serological, or molecular biomarkers have yet emerged to guide clinicians in personalizing treatment for prostate cancer. The intriguing story of AR-V7 suggests that we may be on the cusp of a test that can help distinguish responders to androgen signaling inhibitors from non-responders (Antonarakis E, et al. N Engl J Med. 2014;371: 1028-1038).
AR-V7 is a splice variant of the androgen receptor that lacks the ligand-binding domain—which means that it cannot respond to inhibitors such as abiraterone acetate and enzalutamide. The investigators were able to detect AR-V7 in the circulating tumor cells (CTCs) of 62 mCRPC patients who were treated with either abiraterone or enzalutamide. If AR-V7 was detected in CTCs (about a quarter of the patients), the patients had a 0% PSA response rate to treatment. While those without AR-V7 did not always respond to therapy, the complete lack of clinical response in patients with AR-V7 strongly suggests that such patients would not benefit from abiraterone or enzalutamide.
While this study needs validation as well as a commercially viable platform for dissemination, it does show proof of principle that molecular biomarkers may provide clinically actionable information in managing mCRPC. Avoiding a treatment for lack of efficacy can be just as important as using the treatment because of a proven benefit.
Finally! Promising Results with PDL-1 Antibody in Bladder Cancer
Metastatic bladder cancer is a remarkably treatment-resistant disease. Cisplatin-based combinations have been the standard of care for decades, but are associated with significant toxicity and survival of less than one to two years. Into this desert walks a promising new option: immunotherapy. Powles et al reported results from a Phase I trial of the anti-PD-L1 drug MPDL3280A in urothelial bladder cancer (Powles T, et al. Nature. 2014; 515:558-562). It has been appreciated that cancers evade the immune system in part by expressing PD-L1.
MPDL3280A is an engineered antibody against PD-L1 administered to 67 metastatic bladder cancer patients. Since PD-L1 expression in tumors might predict benefit from this targeted antibody, the investigators reported response to therapy based on PD-L1 expression by immunohistochemistry (IHC). For patients with at least six weeks of follow-up and PD-L1 IHC staining levels of 2 or 3, 43 percent of patients had an objective response, while those with IHC 0/1 had an 11 percent response rate. Two patients had a complete response to therapy and all 17 responders were still on therapy as of the publication of the paper, suggesting durable responses.
Toxicity was mild, with no grade 4 or 5 toxicity and only a four percent rate of grade 3 events. Mild fatigue and decreased appetite were the most common symptoms.
While the jury remains out for how impactful MPDL3280A will be in bladder cancer, the depth and breadth of the responses seen in this report have generated considerable excitement that this agent will improve survival in metastatic bladder cancer. Coupled with its excellent safety profile to date, anti-PD-L1 therapy may represent the most important new drug in bladder cancer in decades.
Links to Studies
Access the hyperlinks (shown in grey) for all the journal studies noted by reading the article on our iPad app, or by reading the pdf of the article on oncology-times.com.