Success of Abiraterone Trials Prompts ‘Mind Shift’ in Prostate Cancer Treatment

The below has been adapted and excerpted from an article in Healio in which Dr. David Nanus HeadshotNanus comments on The LATITUDE and STAMPEDE trials — results of which were presented at this year’s ASCO Annual Meeting and subsequently published in The New England Journal of Medicine. Read the full story here.

Abiraterone acetate is poised to challenge docetaxel as the standard addition to androgen deprivation therapy for treatment of newly diagnosed, metastatic castration-resistant prostate cancer. The LATITUDE and STAMPEDE trials showed the addition of abiraterone acetate and prednisone to androgen deprivation therapy (ADT) reduced risk for death by nearly 40%.

Docetaxel — an IV chemotherapy — can cause nausea, constipation, diarrhea, neutropenia or fatigue during its 18-week dosing schedule. Abiraterone, an oral adrenal inhibitor traditionally used in later-line therapy, is administered until disease progression and has relatively few side effects.

Docetaxel became the standard of care in patients with metastatic hormone-resistant prostate cancer following results from the CHAARTED study, published in 2015 in The New England Journal of Medicine. The results, based on median follow-up of 28.9 months, showed docetaxel improved median overall survival (OS) from 44 months to 57.6 months.

Abiraterone typically has been reserved as second-line therapy for men resistant to ADT. The LATITUDE and STAMPEDE trials — both supported by Janssen, the manufacturer of abiraterone — evaluated whether abiraterone would be more beneficial if used earlier.

Although abiraterone conferred unprecedented survival benefits and is better tolerated, not all oncologists agree it should replace docetaxel in the absence of a head-to-head comparative trial.

HemOnc Today asked urologic oncologists and researchers about the promise of abiraterone; the potential impact of its long-term use; if its cost in comparison with docetaxel is prohibitive; and whether abiraterone soon will be challenged by other therapies for the treatment of metastatic hormone-resistant prostate cancer.

“Abiraterone is a whole new paradigm because your patient is not coming in for an infusion every few weeks for six cycles,” David M. Nanus, MD, professor of medicine and urology at Weill Cornell Medicine, told HemOnc Today. “With six cycles of docetaxel, patients are often wiped out by the time they’re done, and it might take a few months to recover afterward.”

Based on the findings of the LATITUDE and STAMPEDE trials and the potential of targeted therapy, oncologists with whom HemOnc Today spoke agreed researchers are on the precipice of significantly extending the lives of men with prostate cancer.

In addition to the enthusiasm surrounding abiraterone and its potential to be the new standard of care in the treatment of metastatic, castration-resistant prostate cancer, several ongoing clinical trials are investigating other strategies to reduce androgen exposure. Results of those trials also could be practice changing, and again raise questions about the standard of care.

 

Liquid Biopsies in Prostate Cancer: Ready for Prime Time?

Beltran and Lab
(From L to R) Dr. Himisha Beltran, Dr. Raymond Pastore and Dr. Bishoy Faltas

Recent studies in advanced prostate cancer have identified emerging treatment targets and mechanisms of treatment resistance. At the 2017 European Society of Medical Oncology (ESMO) Annual Meeting, Dr. Himisha Beltran chaired and moderated a session evaluating the use of liquid biopsies – blood tests used to glean information about tumors – as a useful clinical tool for prostate cancer management.

While there are no formal guidelines on who, when, how and what to test for in prostate cancer, Dr. Beltran’s expertise provided important guidance to the global oncology community on this topic, as the prospect that a blood test might reveal many insights about the cancer and the tumor makeup has led oncologists to feel excited. Several steps are still needed for broad clinical implementation.

As tumors grow, some of their cells may enter into the bloodstream. These cells are known as circulating tumor cells (CTCs) and travel throughout the body along with fragments of tumor cell DNA known as circulating tumor DNA (ctDNA). Compared with traditional biopsies which extract tissue directly from the tumor, liquid biopsies offer a less invasive way for doctors to detect molecular biomarkers and learn more about what’s going on with someone’s cancer. Liquid biopsies can also better capture tumor heterogeneity, as CTCs and ctDNA can provide a window into the entire tumor (and metastatic sites), compared with a traditional biopsy in which typically only one part of the tumor is sampled. Thus, with a simple blood test, doctors can potentially access a more comprehensive view of an individual’s cancer, which can then help them determine the best treatment for that person. Blood testing can also be more easily repeated throughout the course of treatment in order to monitor disease changes in response to therapy, so liquid biopsy offers ways to detect treatment resistance and resistance mutations early on and throughout the course of the disease.

Red Blood Cells

There is an emerging role for molecular testing in advanced prostate cancer since this information can better inform treatment decisions involving targeted therapies, such as PARP inhibitors, platinum-based chemotherapy, and immunotherapies. Liquid biopsies such as ctDNA may provide information about the genomic alterations present in the cancer, which can be used to help predict how people might respond to certain therapies.

Through liquid biopsies, physicians and researchers can also better detect signs of therapy resistance that may be emerging. For example, if a patient has a gene amplification or mutation detected in ctDNA that involves the androgen receptor (AR) gene, or AR splice variants expressed in CTCs, this may indicate that potent AR-targeted therapies may be less likely to work. This is because the cancer cells may develop various ways to reactivate androgen receptor signaling by acquiring extra copies of the AR gene (gene amplification), activating AR mutations, and/or AR splice variants (such as the AR-V7 variant), all of which result in downstream over-activity of the AR-pathway. Knowing this information up front may spare people from the side effects from a treatment likely to be ineffective. Current research is focused on developing more effective AR pathway inhibitors in this setting. CTCs may also identify other features of the cancer such as localization of the AR in response to taxanes as observed in the TAXYNERGY trial, tumor heterogeneity, and expression of emerging therapeutic targets.

Through a grant from the Prostate Cancer Foundation (PCF), Dr. Beltran and colleagues at WCM are working as part of an international consortium to develop, validate, and implement a ctDNA platform for prostate cancer. This targeted genomic sequencing test, called PCF SELECT, identifies tumor mutations in ctDNA from metastatic prostate cancer patients to guide treatment selection based on precision medicine. It is currently undergoing centralized development, and the long-term goal is that this ctDNA test will be widely used by the clinical prostate cancer community for precision medicine applications.

While liquid biopsies do have promise for these indications and can help guide decisions on the most appropriate treatments for prostate cancer patients, it is important that both patients and clinicians understand the advantages and limitations of available and emerging technologies. Undergoing treatment at a center of excellence that contributes to research on emerging trends allows individuals the opportunity to be among the first to access cutting-edge technologies that may benefit them.

Get Ready for ESMO 2017

The start of fall is here and with the foliage comes a very busy conference season. Up first, we are headed across the ocean to Madrid, Spain for the European Society for Medical Oncology (ESMO) annual meeting from September 8 – September 12.

ESMO LOGO

Our team will be joining nearly 23,000 cancer researchers from 131 countries for this important meeting highlighting the groundbreaking research in cancer. Some of our physicians and scientists from Weill Cornell Medicine and NewYork-Presbyterian will be attending and presenting their research in prostate, bladder, and kidney cancer.

We have a lot to share at ESMO 2017, so please follow along on our social media channels and blog for more updates throughout the weekend and next week.