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.

 

ESMO 2017: Day 2 Recap

IMG_3948The second day of ESMO included the oral genitourinary (GU) oncology session that focused on renal cell (kidney) and urothelial (bladder) carcinoma.

Several years ago, the SWITCH study evaluated the sequence of sunitinib and sorafenib showing similar overall progression free survival and overall survival regardless of the order by which each drug was utilized. At ESMO 2017, results of the SWITCH-II trial were presented. This study tested the sequence of pazopanib and sorafenib in patients with advanced RCC of any histology (i.e. clear cell or non-clear cell).  The study sought to enroll 544 patients, but stopped after 377 patients due to slow accrual. Only half of the patients remained on study and switched to their assigned drug after tumor growth on drug #1. Overall, while the study didn’t complete planned accrual, there was a trend for improved progression-free and overall survival for the pazopanib → sorafenib sequence.

Historically when most patients were treated with cytokines (IL-2 and interferon), two randomized trials by U.S. and European cooperative groups showed that in the setting of metastatic kidney disease, patients live longer by first removing the kidney mass and then treating with interferon rather than treating with interferon without removal of the kidney. Since the introduction of new therapies in late 2005 which have higher rates of tumor shrinkage and longer lifespans for patients, it is unknown if patients should still have their kidney tumor removed prior to drug therapy.

IMG_3954In the EORTC 30073 SURTIME trial, European investigators decided to try to assess whether tumors remained under control longer and patients lived longer if surgery was performed first or if patients initiated sunitinib for 3 cycles prior to cytoreductive nephrectomy. Because enrollment was slow, the study design was changed to assess the percent of patients that were free of tumor progression at 28 weeks. Ninety-nine patients were randomized to immediate versus delayed surgery, most with large kidney tumors and intermediate-risk cancer. Overall there was no difference in the percent with cancer progression at 28 weeks with either approach.  With the caveat of a small study, there were trends for longer survival and less surgical complications in those with delayed surgery. While the amended study is not able to prove that delayed surgery is the better approach, it gives comfort for those physicians/patients that the choice to initiate medical therapy and then re-evaluate for surgery is acceptable. We await the results of the larger CARMENA study that is testing surgery followed by drug versus drug alone (with no surgery) to see if removal of the primary kidney tumor is necessary.

Additionally, two early-phase studies of novel drug combinations of immunotherapy + targeted therapy were presented. In a phase I study led by the NCI, the safety of the combinations of cabozantinib/nivolumab and cabozantinib/nivolumab/ipilimumab were tested in patients with a number of different treatment-refractory tumor types, especially urothelial and other types of bladder cancers. Overall, both combinations were deemed to be safe and are moving forward in a phase III trial. However, many toxicities did occur and most patients needed to reduce the dose of at least one drug so these combinations should only be used in a clinical trial setting.

IMG_3958The phase II portion of a phase I/II study testing the combination of lenvatinib + pembrolizumab. The initial (phase 1) portion of the study presented at ESMO 2016 determined the safe dose in patients with different types of tumors (mostly RCC). This year, new results were presented with 22 additional patients added to the 8 previously treated on the phase I portion. Overall, there was an impressive tumor response rate of 63%, with 83% significant tumor shrinkage in those patients treated in the 1st line setting. This combination is also being tested in a phase III study for patients with advanced RCC which will soon be opening at Weill Cornell Medicine and NewYork-Presbyterian.

Missed our Day 1 Recap of ESMO 2017? Check it out here.

ESMO 2017: Day 1 Recap

ESMO LOGOThe 2017 European Society for Medical Oncology (ESMO) annual meeting has officially kicked off and our team has joined approximately 25,000 cancer researchers from around the world to present and discuss the latest cancer research.

Welcome to ESMO 2017_SignWe’ve outlined some key highlights from the first day of the conference below.

For men with newly diagnosed “hormone sensitive” high risk / advanced prostate cancer, several recent studies have changed the standard of care. Data from the CHAARTED, STAMPEDE, and LATITUDE studies that investigated the addition of docetaxel or abiraterone and low dose prednisone to standard androgen deprivation therapy (ADT) for men with advanced prostate cancer has led to significantly longer and better lives. Updates to this data were presented at ESMO 2017.

The STAMPEDE study included an overlapping period where some men were randomized to ADT + docetaxel chemotherapy and others were randomized to ADT + abiraterone/prednisone. It was comforting to know that whether men received either chemotherapy with docetaxel for 6 cycles or abiraterone and prednisone continuously for at least 2 years that they lived significantly longer compared to men receiving the old standard of ADT alone.

The interesting comparison presented at ESMO 2017 was that men who took abiraterone had longer time to cancer progression (mostly assessed by rising PSA). There were similar overall survival outcomes with either initial treatment strategy. As expected, the types of side effects were different depending upon the type of treatment, but severe toxicity was equally common with either type of treatment.

For the first time, “patient reported outcomes” assessing symptoms and quality of life on the LATITUDE study (including men with high-risk metastatic disease treated with ADT + abiraterone/prednisone or ADT + placebos) were presented. In addition to living significantly longer and having major delays in cancer growth, men taking ADT + abiraterone/prednisone had better pain control and were less likely to have reductions in quality of life, particularly after the initial 4 months on treatment.

Prostate-specific membrane antigen (PSMA) is a protein that is on the cell surface of most prostate cancers and can be used as a treatment target since it is not present many other places in the body. At Weill Cornell Medicine and NewYork-Presbyterian, we have been targeting this protein with radioactive particles for more than a decade. Other institutions have also more recently begun using this approach. Over the past several years, there have been many patients receiving this type of therapy in Europe who may have benefitted from this treatment, but no real prospective clinical trials have been performed. Australian researchers presented data at ESMO in which they enrolled and treated 30 men whose tumors “lit up” on PSMA-PET scans with 177Lu-PSMA-617 in a clinical trial. Patients received up to 4 cycles of therapy. Most patients experienced a significant decrease in PSA, some had tumors shrink on scans, and severe side effects were limited.

We have previously published on the (initially) surprisingly high frequency of inherited “germline” alterations in men with advanced prostate cancer. A Spanish group performed a prospective study of 419 men and found that about 9% had alterations in genes that affect the body’s ability to repair damaged DNA. Among the 6.2% with the most common alterations – BRCA2, ATM, and BRCA1  — overall survival was not significantly shorter compared to men without these genetic mutations. However, when examining just the most common BRCA2 gene, men did not live as long. Whether or not these inherited DNA alterations were present, men could respond to approved therapeutic agents, so if clinical trials are not available men should be encouraged to take standard hormonal or chemotherapy.