Tag: Trials

New Clinical Trial Open for Men with Prostate Cancer

lab-researchProstate cancer grows and spreads via the androgen receptor (AR) pathway. In the beginning of treatment, most men with prostate cancer respond to androgen deprivation therapy (ADT) which cuts off this pathway. Unfortunately, the tumors are smart and evolve to create work-arounds. As a result, most men become resistant to this treatment. We call this later, more evolved form of prostate cancer, castration-resistant prostate cancer (CRPC), as it is molecularly different from the initial tumor.

taxane-figure-with-backgroundTaxane chemotherapies – docetaxel and cabazitazel– are the only treatments to demonstrate a survival benefit in men with CRPC. At Weill Cornell Medicine and NewYork-Presbyterian, we have shown that the mechanism of docetaxel taxane action in prostate cancer is inhibiting the androgen receptor pathway on the cellular level by preventing the cancer cells from being able to communicate with other cancer cells using microtubules. Dr. Scott Tagawa explains our prior research in the below video. This suggests that docetaxel may complement other therapies that target the AR pathway, including hormonal-based therapies such as ADT.

Recent trials of docetaxel plus ADT validated our scientific findings, demonstrating very impressively significant improvement in survival in men with metastatic prostate cancer who had not previously received hormonal therapy (also known as hormone-naïve metastatic prostate cancer). Taken together, these studies in both hormone-naïve and CRPC suggest that combining drugs that independently target AR signaling (what the scientific literature refers to as forming a “vertical pathway blockade”) will be more effective than sequentially using these treatments to combat the spread of the cancer.

Our recently-opened phase I study combines the approved 1st line taxane chemotherapy (docetaxel), approved potent inhibitor of testosterone production (the CYP17 inhibitor abiraterone) and a novel AR signaling inhibitor (apalutamide) in men with chemotherapy-naïve metastatic CRPC.

We hypothesize that combining these three agents that all target the same pathway using different mechanisms will result in a synergy that leads to improved cancer outcomes. We previously reported the safety and initial efficacy results of docetaxel plus abiraterone in a multicenter study. The combination was well tolerated and the preliminary efficacy results were promising, confirming the enthusiasm in the prostate cancer community to explore “early” chemotherapy combined with AR-targeted therapy for mCRPC.

As in all phase I clinical trials, there are two aims to this study. The first will provide safety and preliminary efficacy data on this combination treatment. Additionally, we will be performing molecular analysis of blood/tumor samples to identify biomarkers that are able to help predict which patients are most likely to respond to treatment, as well as to determine why some cancers become resistant to treatment. This would allow us to develop biomarker-driven clinical trials that have the potential to shift the treatment paradigm and improve outcomes for men with advanced PC.

To learn more about this clinical trial or to make an appointment with a physician in the Weill Cornell Genitourinary (GU) Oncology program, please call 646.962.2072.

Immunotherapy and Prostate Cancer: What You Should Know

Cancer CureImmunotherapy, broadly defined as using the body’s own immune system to fight cancer, is one of the most exciting developments in cancer care. In oncology, for some patients using an immunotherapy treatment approach has resulted in some deep and prolonged responses.

The field of genitourinary (GU) oncology one was of the first sub-specialty areas to utilize immunotherapy and compared to many other tumor types, GU oncology has been using it for the longest amount of time — particularly for kidney (renal) and bladder cancers. There have been more recent advances across the board in immunotherapy, including the approval of atezolizumab by the FDA for bladder and urothelial cancers, marking the first new treatment for that tumor type in nearly three decades. Additionally, in select patients who have advanced urothelial cancer that has not responded to platinum-based chemotherapy, adding immunotherapy with pembrolizumab to the treatment regimen improved survival.

In the modern treatment era, prostate cancer was one of the first cancers to show a survival advantage with immunotherapy, specifically sipuleucel-T. Also known by the brand name Provenge, sipuleucel-T stimulates the immune system to seek out cancer cells and attack them. It represents the first therapeutic cancer vaccine in any cancer (treatment-focused as opposed to prevention-focused), and is FDA-approved for men with metastatic hormonal-resistant prostate cancer (mCRPC). Unfortunately, not all men respond to this treatment. At Weill Cornell Medicine and NewYork-Presbyterian, we are looking to improve responses to sipuleucel-T with our Newlink-sponsored study of sipuleucel-T followed by indoximod/placebo. In addition, since it is difficult to tell which patients are the best fit for this treatment and which ones are responding to sipuleucel-T, we continue collaborations with other researchers to work on developing blood tests to find biomarkers to help men in the future.

Additionally, recent data from the 2016 European Society of Medical Oncology (ESMO) annual meeting demonstrated promising results for using pembrolizumab (also called Keytruda) in metastatic hormonal resistant prostate cancer. This immunotherapy that works by inhibiting the PD-1 pathway and has been recently approved in other tumor types, such as melanoma and lung cancer. An initial study of the drug across different tumor types was highlighted at the ESMO meeting with significant responses in a proportion of men with prostate cancer whose cancers grew despite essentially all known therapies. In addition, a study influenced by and subsequently performed by different groups of WCM collaborators demonstrated that five men with progressive metastatic castration-resistant prostate cancer had major responses to this immune therapy, with PSA’s dropping by more than 99% and tumors greatly shrinking on scans. While all types of immunotherapy can lead to serious side effects, the treatment was generally very well-tolerated with minor side effects.

We are continuing the work to further define the subsets of men with advanced prostate cancer who can benefit from immunotherapy and we have a newly opened study of pembrolizumab for men with mCRPC. In this study, three groups of men will receive open-label (i.e. no placebo) pembrolizumab to test efficacy as measured by tumor shrinkage. We will also assess PSA changes and duration of tumor response, as well as biomarkers to help us determine in the future which men will receive the greatest benefit from this treatment.

Another promising immunotherapy-based prostate cancer treatment uses the monoclonal antibody (mAb) J591. J591 can recognize a protein antigen known as PSMA (also known as anti-prostate-specific membrane antigen) that is expressed on virtually all prostate cancer cells, and more heavily expressed in men with treatment-resistant metastatic forms of the disease. At the recent ESMO conference, we presented two clinical trials of J591 immunotherapy that are currently in progress here at Weill Cornell Medicine and NewYork-Presbyterian. One is for men with advanced prostate cancer and high (unfavorable) circulating tumor cell (CTC) count and the other delivers two doses of J591 prior to prostatectomy for men with intermediate and high risk prostate cancer. These trials are based upon the prior track record of this antibody in men with prostate cancer, including the fact that in initial pilot studies, men with advanced prostate cancer and a high number of CTCs had a decrease in tumor cell counts after J591. In addition, a prior study of J591 in combination with low-dose interkeukin-2 (IL-2) indicated that men with biochemically recurrent prostate cancer (rising PSA) did not develop metastatic disease as would have been expected without this intervention, and those with metastatic castration-resistant prostate cancer lived significantly longer than expected.

We also continue to utilize antibodies to deliver chemotherapy or radioactive particles to tumor cells with the intent of sparing normal cells. Three of these types of immunotherapy studies are currently enrolling for men with advanced prostate cancer, with others in development.

  • IMMU-132: This compound consists of a drug attached to an antibody which recognizes Trop2, a target that is over-expressed on prostate cancer cells. The antibody carries SN38, the active ingredient in irinotecan, which has shown prior responses in solid tumors. The drug has shown promising activity in breast and bladder cancer and is now being studied in prostate cancer.
  • Rovalpituzumab Tesirine “Rova-T” in Delta-Like Protein 3 (DLL3)-Expressing Advanced Solid Tumors: Our research has demonstrated that neuroendocrine prostate cancer (NEPC), one of the most aggressive and treatment-resistant prostate cancer subtypes, highly expresses DLL3. Rova-T uses an antibody to hone in on cells with DLL3 and take along a potent toxin to target those specific cells.
  • 177Lu-J591 + ketoconazole: In this clinical trial, J591 is radiolabeled with 177Lutetium, (177Lu) in order to deliver the drug directly to the prostate cancer cells. It is given in combination with an oral hormonal therapy drug which both attacks prostate cancer and at the same time, increases expression of PSMA, which is recognized by J591, leading to more targeting of the otherwise invisible tumor cells.

Promising Research Brings New Hope for Men with Aggressive Prostate Cancer

misha-beltra_esmo_img_2611Earlier this month, Dr. Himisha Beltran presented exciting new research results for those with metastatic prostate cancer at the European Society of Medical Oncology (ESMO)’s annual meeting in Copenhagen, Denmark. Cancer experts and patients from around the world came to the 2016 ESMO Congress to discuss the latest research and cutting-edge treatment options for people with cancer.

Dr. Beltran’s research presentation highlighted promising results from a clinical trial for men with aggressive prostate cancer. Aggressive prostate cancer sub-types represent approximately 25% of all prostate cancer cases, and neuroendocrine prostate cancer (NEPC) is considered to be the sub-type that is most resistant to currently-available treatments.

Dr. Beltran and the Weill Cornell Medicine (WCM) Genitourinary (GU) Oncology team led this multicenter, phase 2 clinical trial, which was based upon prior WCM work which identified aurora kinase A as a key target in NEPC. The trial enrolled sixty patients from across the United States. It was the first clinical trial to study a new, targeted treatment for men with NEPC. The drug used in this study, Alisertib, is an oral medication that is an Aurora Kinase A Inhibitor.

This clinical trial confirmed our hypothesis that different men’s tumors genetically expressed different levels of the targets for the drug, and as a result their response rates to this treatment varied. Those with the most optimal responses had cancers that genetically appeared to be most like NEPC in both biopsies and whole exome genomic sequencing of the tumor. As part of our Institute for Precision Medicine, we use the Exact-1 whole exome sequencing test to categorize more than 21,000 genes within the tumor. This is the most comprehensive way to determine where mutations and mechanisms for treatment resistance may exist in patients with advanced stage cancer and allows us to narrowly target different patient’s treatment regimens on the molecular level. In addition, some of the tumor biopsies were analyzed for gene expression (RNA) and organoids, which are tumor models that we are able to grow from the biopsy tissue, were developed.

In this clinical trial, we were able to learn a lot on the molecular level from the patients who had the most exceptional responses to Alisertib. Based on these results and establishing biomarkers to predict Alisertib response rates, future clinical trials could be much more targeted to include only the men whose tumors indicate that they are likely to respond to this therapy.

Additionally, there is great potential to learn much more about the tumor evolution and the biology of resistance. This clinical trial underscores the need to more narrowly focus on the sub-set of prostate cancer patients with NEPC, as there are few standard treatment options and limited clinical trials available for these men.

Thank you to all the men who enrolled in this clinical trial and helped further the field of research in the search for new cures for prostate cancer.

We’re always working to increase access to new promising treatments for NEPC and other aggressive forms of prostate cancer through clinical trials. To learn more about our open studies and to make an appointment with the Weill Cornell Genitourinary (GU) Oncology Program, call 646-962-2072.

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