ESMO: Day 3 Recap

At ESMO 2017, Sunday, September 10th was the day with the largest number of genitourinary (GU) cancer presentations, including two kidney cancer and urothelial cancer highlights in the Presidential Symposium, many poster presentations, and two poster discussion sessions. We’ve broken down the full day of research updates by cancer type.

Kidney Cancer

ESMO_CheckMate 214In the Presidential Presentation on kidney cancer, results were presented from the CheckMate-214 trial. Nivolumab is an anti-PD1 antibody approved for patients with advanced renal cell carcinoma (RCC) previously treated with a VEGF-targeted therapy based upon a randomized trial demonstrating an overall survival benefit. The combination of using immune checkpoint inhibitors transitioned from laboratory science to safety studies to full approval in melanoma based upon randomized trials. The CheckMate 214 study tested the efficacy of the combination of nivolumab plus ipilimumab versus one of the most standard VEGF multikinase inhibitors, sunitinib, in previously untreated patients with advanced RCC. The study focused on the intermediate/poor risk population, but also enrolled patients with good risk disease. The study met its endpoints in an impressive fashion. In the target intermediate/poor risk population, the immune checkpoint inhibitor combination led to an improved response rate and overall survival benefit versus the active drug sunitinib. Nine percent of patients had a “complete response” with the combination immunotherapy (meaning complete disappearance of all evidence of cancer on scans). In addition, the entire patient population (with patients in all prognostic groups combined) experienced an improvement in both response and overall survival with immunotherapy.  There were some interesting exploratory analyses of subgroups and the PD-L1 expression status that will lead to additional investigation, but the study will lead to a paradigm shift and create a new standard of care for patients with advanced RCC.

In the Alliance-led A031203 “CaboSun” study, patients with intermediate and poor-risk advanced renal cell carcinoma (RCC) were randomized to receive either cabozantinib or sunitinib. The initial results of the study as assessed by the investigative team showed a benefit of cabozantinib over sunitinib in terms of the trial’s primary endpoint of overall survival. One previous caveat of the study was that interpretation of scans by investigators who are also the treating physicians can be biased. An updated analysis added independent review of scans as well as longer follow up. The progression-free survival benefit of cabozantinib was confirmed by independent review and the magnitude of benefit was increased with longer follow up.

Approximately a third of patients with advanced RCC have bone metastases and this may be a negative indicator of prognosis (also known as a “negative prognostic factor”). Radium-223 is an FDA approved agent for men with metastatic castration-resistant prostate cancer and predominant bone metastases that has been shown to benefit overall survival. A team of investigators from Boston assessed whether adding radium-223 to standard sunitinib or pazopanib would also benefit patients with kidney cancer. The combined treatment was determined to be safe and and markers in the blood and urine indicating that the bone is breaking down – a measure of bone metastases – improved with treatment. Additional randomized trials are needed to assess the true effect of this combination on overall survival.

Bladder and Urothelial Cancer

ESMO_RANGEDuring the ESMO Presidential Presentation on urothelial cancer, results from the RANGE clinical trial were presented. The utility of chemotherapy is limited in patients with advanced urothelial carcinoma whose cancer has progressed after initial platinum-based chemotherapy. Ramicurimab is a monoclonal antibody against the angiogenic factor receptor VEGF-R2. We performed a randomized phase II trial pointing towards a response and progression-free survival benefit with the addition of ramicurimab to docetaxel chemotherapy in this patient population. The RANGE study is a phase III study in which patients with advanced platinum-resistant urothelial carcinoma, with or without treatment with an immune checkpoint inhibitor, were randomized to docetaxel with ramicurimab or placebo. This phase III trial confirmed the benefit of ramicurimab when added to docetaxel in improving progression-free survival and response rate. In addition, there was no significant additional toxicity with the combination, also referred to as a doublet. We await the final overall survival results and additional analyses to assess the place of this combination in our growing treatment armamentarium for urothelial carcinoma.

Several studies examined the genetic material (genome) of tumors in patients with urothelial carcinoma. In a large clinical trial including more than 2000 patients with advanced urothelial carcinoma, investigators utilized the FoundationOne platform to assess the tumor genome of a mix of primary and metastatic tumors arising from the bladder, renal pelvis, and ureters. The study described the landscape of this disease using the targeted sequencing platform, showing a relationship between some common alterations (such as genes for Her2 and PI3K) and a higher rate of overall mutations or “tumor mutational burden” (also referred to as “TMB”).  An analysis of the Checkmate-275 study which led to the approval of nivolumab in patients with progressive urothelial carcinoma after chemotherapy looked at tumor mutational burden and survival outcomes. Higher tumor mutational burden was associated with both better response and survival in patients treated with nivolumab, a form of immunotherapy called an anti-PD1 checkpoint inhibitor. This result was independent of PDL1 status – a specific measure of this a type of mutational burden–  but perhaps stronger in PDL1 low tumors.

Dr. Scott Tagawa, Medical Director of the WCM/NYP Genitourinary Oncology Program, presented a research update regarding patients with advanced urothelial carcinoma who were treated with sacituzumab govitecan (IMMU-132)  after prior chemotherapy. This drug, which links an antibody against Trop2 (which is usually present to a high degree in urothelial carcinoma compared to normal cells) to a potent chemotherapy metabolite, was administered to 41 patients with cancer progression despite an average of three prior treatment regimens. Significant tumor shrinkage (i.e. partial or complete responses) occurred in 34% of patients. In addition, median progression free survival of approximately 7 months and overall survival of approximately 16 months was impressive compared to the expected rates for this patient population.

Prostate Cancer

Prior prostate cancer research has demonstrated strong links within family trees, and as a result, there has been a large push for research to identify where exactly in the genetic profile this risk comes from and whether these genes are passed down through ancestry. In the UK Genetic Prostate Cancer Study (UKGPCS), investigators performed a case-control study of men with and without germline (inherited) DNA damage response and repair genes (those responsible for repairing the DNA of cells in the body) identified in their 167 gene panel. Like in other studies, those with germline alterations had worse cancer-specific outcomes and overall survival rates. Notably across studies, the presence of these inherited genes is not limited to men diagnosed at an early age, so a discussion with physicians about the risks/benefits of genetic testing should be considered.

Our collaborator Dr. Armstrong of Duke University presented research analyzing PSA changes in the PREVAIL trial which led to the FDA-label expansion of enzalutamide for men with mCRPC and no prior chemotherapy. As he and others have previously demonstrated with other drugs such as docetaxel and abiraterone, a lack of PSA decline while on treatment was associated with a poor outcome.

ESMO_ValeTwo presentations focused on men with hormone-sensitive high risk and advanced prostate cancer.

Dr. CL Vale from the UK presented an analysis of data available from randomized trials which pointed towards abiraterone + androgen deprivation therapy (ADT) having a large early relative survival benefit of 37% after 3 years, and docetaxel + ADT having a smaller, but still large and significant 23% survival impact after additional follow up for 4 years.

In prostate cancer, there is a “TNM” staging system that indicates the size range of the primary tumor (T), whether the cancer has spread to the lymph nodes (N), whether there are signs that the cancer is metastatic and has spread elsewhere in the body (M). When there are no signs of distant metastases, the corresponding staging is “M0” which translates to M zero, or no metastases. ESMO_M0_ProstateCancer

Dr. Nicholas James from the UK presented data on the “M0” population of 915 men without distant metastatic disease receiving abiraterone + ADT versus ADT with or without radiation as part of the STAMPEDE study. In the overall group with M0 disease, so far there have not yet been any detectable differences in survival, which is not surprising since this subset of men tend to live for a long time while on therapy. There were though, important improvements in the amount of time to cancer growth or the development of metastatic disease. In those men with clinically evident lymph node metastases at diagnosis (corresponding to the symbol “N”), the combination of all three treatments — abiraterone, ADT, and radiation — demonstrated a significantly better survival benefit than those treated with ADT + radiation, which was in turn better than ADT alone.

Additionally, new information on interesting early phase clinical trials was also presented at ESMO.

At Weill Cornell Medicine and NewYork-Presbyterian, we participated in a clinical trial utilizing INO-5150, a DNA vaccine against PSA and PSMA. This vaccine was administered with electroporation (essentially a small electric shock at the injection site) and with or without INO-9012 (an IL-12 vaccine) designed as an adjuvant treatment to improve immune responses to the INO-5150 treatment. Men who received either one or both vaccines had few side effects other than skin reactions at the injection site and many developed immune responses. Additional study is warranted to test anti-tumor efficacy.

EC1169 is comprised of a small molecule PSMA ligand linked to a tubulysin drug. Updated data were presented in this trial where men with metastatic castration resistant prostate cancer (mCRPC) who had both received and not received prior chemotherapy were treated with EC1169. As more men were treated on trial, researchers were able to document safety and tolerability of the drug, while demonstrating the drug’s ability to control the cancer, particularly in men who had previously received docetaxel chemotherapy.

In prostate cancer, one of the mechanisms of resistance to hormonal therapy is activation of the PI3K/AKT pathway. GSK2636771 is a PI3K inhibitor that was tested in a phase I study by adding the drug to enzalutamide in men with mCRPC who had experienced some cancer progression while taking enzalutamide alone. Importantly, the trial demonstrated that GSK2636771 was safe and a signal of efficacy was present in the small trial. Additional studies are planned which will be adding the drug to enzalutamide to truly test its ability to control cancer growth. Of note, the PI3K pathway is indicated in the formation and growth of numerous cancers and was discovered by our cancer center director, Lewis Cantley, PhD.

Check out our prior ESMO 2017 Day 1 and Day 2 Recaps.

2017 Genitourinary Cancers Symposium

gu_symposium_2017_img_3054The 2017 Genitourinary (GU) Cancer Symposium kicked off on February 16th in Orlando, Florida, bringing together more than 3,000 attendees from all over the world. At this annual conference, clinicians from a wide range of disciplines treating people with prostate cancer, kidney cancer, bladder cancer, and testicular cancer come together to hear from experts on the latest scientific discoveries and how they impact clinical care for patients.

The Weill Cornell Medicine (WCM) and NewYork-Presbyterian (NYP) GU Oncology team is down in the Sunshine State highlighting the cutting-edge research and patient care that has been taking place back on campus in New York City.

twitter-iconTeam member Dr. Bishoy Faltas was selected by the conference to be a “Featured Voice” on Twitter, so be sure to follow him (@DrFaltas) for updates in real-time. Dr. Scott Tagawa (@DrScottTagawa) is now on Twitter too and also tweeting live from the symposium. The official conference hashtag is #GU17.

Some #GU17 highlights

Day 1 – The initial session focused on active surveillance for prostate cancer, including using both imaging as well as tissue biomarkers to help select optimal patients for surveillance versus those who should undergo surgery or radiation. A subsequent session focused on prostate cancer that progresses despite therapy and the pathways of resistance that can develop. This included a discussion of prostate cancer subtypes that become independent of the androgen-receptor (hormonal) pathway, including aggressive variant and neuroendocrine prostate cancer (NEPC). Neuroendocrine prostate cancer is one of the most aggressive and treatment-resistant types of prostate cancer that most often evolves from prior hormonal therapy.

beltran-attard
Dr. Misha Beltran and Dr. Gerhardt Attard are two of the primary investigators for the 2016-2018 Movember Foundation-PCF Challenge Award

Dr. Gerhardt Attard at the Institute of Cancer Research in London, gave a great talk on the value of circulating tumor DNA in prostate cancer. He spoke about the collaborative grant from the Movember Foundation and the Prostate Cancer Foundation (PCF) that he, Dr. Misha Beltran and others have used to develop signature ways to confirm neuroendocrine prostate cancer with a blood test. An additional collaborative grant will allow optimization of this technology across a larger number of centers. Learn more about this prestigious Movember Foundation-PCF Challenge Award and how we’re using genomic characterization of tumors in less invasive ways in order to bring precision medicine – or narrowly tailored, personalized treatment – to more patients.

evi_taxynergy_gu-symposium_jpgDr. Evi Giannakakou explains to a crowd of physician-scientists results from our TAXYNERGY clinical trial showing additional evidence of using cancer cells circulating in the blood, also referred to as circulating tumor cells or CTCs, as a primary biomarker for chemotherapy response. This research validated prior work regarding the mechanism of action of chemotherapy in prostate cancer and demonstrates that using a simple blood draw, within one week of first chemotherapy treatment, we’re able to determine whether men with metastatic prostate cancer have a higher chance of responding. In the future, this might spare men from additional treatment (with associated side effects) with a drug that has a lower chance of working. For additional background information on this research, check out our prior in-depth blog post on the topic.

jok9106Dr. Josephine Kang, a radiation oncologist at WCM/NYP, presented a poster on Stereotactic Body Radiotherapy (SBRT), which is an emerging treatment modality with excellent control rates for low- and intermediate-risk prostate cancer. The role of SBRT for high-risk prostate cancer has not been studied as closely, but this trial showed encouraging results for those with high-risk disease. These results are very encouraging, as the treatment can be completed in 5 treatments. Additionally, this data longitudinally followed men treated with this modality for 7 years, and it appears to be a safe and effective treatment for high-risk prostate carcinoma. SBRT may be a good treatment alternative particularly for patients unable to undergo hormonal therapy (androgen receptor therapy/ADT) or unwilling to receive standard 8-9 week radiation therapy. More research is ongoing. Learn more about our open clinical trial using this modality. Another study will soon be opening.

In the oral abstract session, data was presented from a cooperative group trial that the older chemotherapy drug mitoxantrone should not be used immediately following surgery. Assays from biopsy material can separate different classes of prostate cancer with different risk for inferior outcomes. Blood biomarkers utilizing circulating tumor cells appear to be prognostic and potentially predictive of response to certain drugs. We are currently participating in a study to validate this data across multiple institutions and technology platforms.

In the keynote lecture, Dr. Charles Drake who recently joined the NYP family at Columbia discussed the current status and future directions of immunotherapy for prostate cancer.

Stay tuned for additional updates throughout the symposium!

Should Men with Metastatic Prostate Cancer Get Genetic Testing?

DNA Helix_NCI
DNA Helix (Photo Credit: National Cancer Institute)

Of all the different types of cancer, prostate cancer is one with some of the strongest links to the family tree. The inherited risk of developing prostate cancer due to genetic factors has been estimated to be as high as 57%. As a result, there has been a large push for research to identify where exactly in the genetic profile this risk comes from and whether these genes are passed down through ancestry.

We already know that mutations in certain genes – specifically those that are responsible for repairing the DNA of cells in our body – can increase cancer risk. A gene mutation like this disrupts the normal function of the genes involved in repairing damaged DNA, and so far, more than 100 variants have been found. These include mutations in BRCA1, BRCA2, MSH2, and HOXB13. The most common mutation of this type is involves the BRCA2 gene, which is linked with significantly increased risk of cancers of the breast, ovaries, prostate, colon, pancreas, as well as melanoma. It is linked with 1.8% of overall prostate cancer cases.

Weill Cornell Medicine and NewYork-Presbyterian served as one of the main research sites in a recently-published multi-institutional study which found that 11.8% of men with metastatic prostate cancer had DNA-repair gene mutations. This is significantly higher than the prevalence among men with localized prostate cancer (4.6%). These mutations are associated with more aggressive and fatal cancers, so it makes sense that a higher percentage was found in those with metastatic disease.

This study also showed a link between having DNA-repair mutations and a family history of prostate cancer. Genetic testing is very important because inherited mutations in genes that affect DNA repair plays an important role in identifying family members who also may be at increased risk (and not just for prostate cancer), deciding the best course of treatment, and in decision making in screening for other cancers. Knowing this information presents an opportunity for precision medicine in order to customize treatment for each patient.

PARP1 is an enzyme that has emerged as a new drug target for cancer therapy and certain cancer treatments, such as PARP1-inhibitors have been shown to be more effective in prostate cancer patients with these DNA-repair mutations. Men with metastatic prostate cancer and these mutations also frequently respond to platinum chemotherapy.

Additionally, it is known that twins are more affected and early-onset cancer may result from germline alterations so young men with prostate cancer are being studied to figure out which genes may be linked with a prostate cancer diagnosis at an early age.