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.

 

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.

Thinking Beyond Survival – Cerebrovascular Complications of Cancer

Babak Navi_headshotBabak B. Navi, MD, MS
Stroke Center Director
Assistant Professor of Neurology
Weill Cornell Medicine | NewYork-Presbyterian

Over the past decade, there has been tremendous progress in cancer therapeutics. This includes targeted agents that act on specific receptors in cancer cells, immunotherapy which harnesses the body’s immune system to attack cancer cells, and personalized medicine whereby oncologists use different combinations of cancer drugs to optimize the chance of success based on the molecular profile of the tumor. These amazing scientific advances have led to prolonged survival for people with several cancer types, and it is possible that in the not-too-distant future, cancer will become more of a chronic disease with periodic flare-ups similar to what has occurred with diabetes and HIV. However, with this paradigm shift, long-term quality of life and well-being has become more important, and preventing diseases and complications that can affect these factors is paramount.

Stroke is the leading cause of disability in the United States. In addition, in many parts of the world, including Asia, it is the leading cause of death. In the United States alone, 800,000 people each year suffer stroke and this number is expected to rise as average life expectancy increases. Many factors can increase a person’s risk for stroke including age, hypertension, diabetes, high cholesterol, obesity, and smoking. Besides these traditional stroke risk factors, we now know that cancer and its treatments also increase the risk of stroke. In particular, patients with certain types of cancer, such as lung, pancreatic, and bladder cancers, as well as patients with metastatic disease, tend to have the highest risk. For instance, elderly patients with newly-diagnosed lung cancer face roughly an 8% risk of stroke in the first year after being diagnosed with cancer. In addition, cancer patients’ stroke risk varies with time and is highest in the first 3 months after diagnosis, when some cancer patients face up to a 3-fold higher risk of stroke than usual. It also turns out that certain necessary and potentially life-saving cancer treatments, including some forms of chemotherapy and radiation, can increase stroke risk.

At the moment, the exact reasons why cancer patients face a heightened risk of stroke are unclear. It is well known that circulating cancer cells can alter individuals’ clotting systems to promote clot formation but exactly how they do this is uncertain. Furthermore, doctors know that certain chemotherapy and radiotherapy treatments can damage blood vessels, but once again, the exact mechanisms underlying these processes are poorly understood.

At Weill Cornell Medicine and NewYork-Presbyterian, my team is actively working to determine what the exact risks of stroke are in people with newly diagnosed cancer, what clinical factors and biomarkers in blood can help doctors identify high-risk patients, and what the optimal strategies are to prevent and treat stroke in cancer patients. One particular study that we are currently enrolling into is entitled MOST-Cancer. This study uses cutting-edge ultrasound and blood tests to evaluate the predictors and mechanisms of stroke in people with cancer. If you or a loved one has cancer and are interested in learning more about these studies, please email our team at stroketrials@med.cornell.edu or call 212-746-6757.

May is National Stroke Awareness Month. The main intent of this campaign is to raise awareness about the symptoms and signs of stroke and to educate the public to call 911 if they suspect stroke. The most popular campaign is FAST, which stands for Face, Arm, Speech, and Time – Time to call 911.

If you or a companion develops unexplained facial asymmetry, arm weakness, or speech changes, you should call 911 immediately so that an ambulance is activated to provide rapid delivery to the closest stroke center. This is imperative as there are medicines and surgical procedures that have been proven to improve outcomes after stroke but these are only effective in the first few hours after stroke onset. Therefore, if stroke is suspected, do not hesitate, call 911, as it could be life saving!

Furthermore, I recommend that cancer patients have a frank discussion with their doctors about their individual risks for stroke and other cardiovascular diseases, as well as potential strategies to reduce their risks through medicines and lifestyle modifications.

We’ve made great strides in oncological care so that patients routinely get cured or live many years with their disease. Therefore, it is now time that we turn our attention to long-term quality of life, and in particular, to preventing stroke and the other secondary complications of cancer.

Stroke_BE FAST SIGN NEW