Burgess Shares Insight on Evolving Prostate Cancer Paradigm

Earle Burgess, MD

Recent clinical trials and regulatory decisions have shifted treatment for patients with metastatic castration-sensitive prostate cancer, but tireless research needs to continue until curative strategies emerge, said Earle Burgess, MD.

One of the latest advances was the February 2018 FDA approval of abiraterone acetate (Zytiga) in combination with prednisone for patients with high-risk disease. This approval was based on phase III findings from the LATITUDE study.

In the trial, the combination of abiraterone acetate and androgen deprivation therapy (ADT) led to a 38% reduction in the risk of death compared with ADT alone. After a median follow-up of 30.4 months, median overall survival (OS) was not yet reached with abiraterone acetate compared with 34.7 months with placebo for patients with high-risk metastatic castration-sensitive prostate cancer (HR, 0.62; 95% CI, 0.51-0.76; P <.001).

Additionally, based on data from the CHAARTED and STAMPEDE studies, docetaxel has continued to show encouraging results when combined with ADT as a frontline treatment of this patient population.

OncLive: What have been some impactful trials in metastatic castration-sensitive prostate cancer?

In an interview at the 2018 OncLive^® State of the Science Summit™ on Genitourinary Cancers, Burgess, an associate professor of medicine at Levine Cancer Institute, Atrium Health, discussed the shifting paradigm of metastatic castration-sensitive prostate cancer.Burgess: Four years ago, we learned that the addition of docetaxel to ADT for patients with newly diagnosed castration-sensitive prostate cancer improves survival and secondary endpoints. The CHAARTED trial was the key study here. It was a randomized phase III study that confirmed the benefit for docetaxel. The STAMPEDE trial was a multi-arm study run out of the United Kingdom that included multiple different therapeutic interventions. It confirmed the findings of CHAARTED—the survival benefit with the addition of docetaxel.

Could you explain the synergy between abiraterone acetate and prednisone?

Do you see a role for immunotherapy in prostate cancer?

How much of a challenge is it to sequence these therapies?

What does a diagnosis of prostate cancer mean today versus 5 years ago?

Are there any specific ongoing trials or therapies you want to highlight?

What area of prostate cancer needs the most research?

Separate from that, abiraterone acetate has been tested in combination with ADT for this space. The LATITUDE study was a randomized phase III trial, which showed that abiraterone acetate improved OS. Abiraterone was first developed in the castration-resistant setting. We know that in a castrated patient, when testicular androgen production has been stopped, prostate cancer can still grow and progress. Abiraterone acetate essentially shuts off adrenal steroidogenesis. It was shown to improve survival in castration-resistant patients. For that reason, it's a natural synergy with ADT. I do. At the 2018 ASCO Annual Meeting, we learned that there clearly is a small subset of patients with advanced disease that will benefit from immunotherapy. It seems to be enriched in the population that has homologous recombination repair defects. This is particularly true in patients with microsatellite instability-high tumors. We are also learning about the role of CDK12 in prostate cancer. We know from early data that CDK12 may increase sensitivity to immunotherapy. That has not yet been tested in a large clinical trial. This is an important point. When patients are first diagnosed, we are trying to learn as much as we possibly can about that particular tumor, specifically germline status. We know which patients are starting to respond to PARP inhibitors, as I just mentioned. It is important to track this early in the course of the disease. The more we know about the molecular profile of the tumor, the easier sequencing becomes. The advancement and options we have are allowing patients to live longer with a much better quality of life (QoL). With the drugs currently in development, and with our better knowledge of the disease, we will create even more personalized therapy. Outcomes are better, tolerability is better, and we're just moving forward. There are so many. The biggest thing right now is the PARP inhibitors. There is a lot of ongoing research in that space and we are eagerly awaiting the results. Those are of the most interest. Another big question is if we can build on what we learned from CHAARTED, STAMPEDE, and LATITUDE and develop combination therapies. At the end of the day, we are not curing these patients. Therefore, there is always going to be that unmet need until we can get there. The highest-risk patients are the ones with advanced metastatic castration-resistant disease. We need to come up with something that is going to prolong the survival and QoL of these patients.

Fizazi K, Tran N, Fein LE, et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017;377(4):352-360. doi: 10.1056/NEJMoa1704174.