ASCO 2017: Genitourinary (GU) Oncology Highlights

ASCO Logo PhotoEach year, the American Society of Clinical Oncology (ASCO) Annual Meeting brings together more than 30,000 oncology professionals. At this year’s meeting in Chicago, physicians and scientists presented the latest research findings in an effort to bring the best cancer treatments to patients across the United States and the world. We’ve outlined some of the genitourinary (GU) oncology highlights, broken down by disease type.

At this year’s meeting, there was also some important research presented related to communication, quality of life and survival. In a study that involved patients with GU cancers, as well as those with other types of tumors, patients were randomized to two groups: 1) a control group of standard care 2) a group to utilize a web-based patient-reported outcome questionnaire between visits. Results from any answers completed in the online system were sent to the treatment team in real time. In this study, the patients that were randomized to the online questionnaire group experienced better quality of life. In addition, these patients lived longer, with a 17% improvement in survival simply by using the online tracker reporting symptoms to their treatment team between visits. While the study was only conducted at a single institution, it underscores the importance of communicating and relaying any symptoms to your treatment team members responsible for your medical care (generally physicians, nurses and advanced practitioners).

Prostate Cancer:

The results from two large phase 3 clinical trials will lead to a change in the standard of care treatment for men with advanced prostate cancer. The LATITUDE and STAMPEDE trials investigated the addition of abiraterone and low dose prednisone to standard androgen deprivation therapy (ADT) for men with advanced prostate cancer. Similar to the unprecedented results presented at ASCO in 2014 (CHAARTED) and 2015 (STAMPEDE) with the use of docetaxel chemotherapy, a major improvement in overall survival was demonstrated, improving length of life by nearly 40%. The results from these studies will provide an additional treatment option for men presenting with advanced prostate cancer.

For men with metastatic castration-resistant prostate cancer (mCRPC), a randomized phase 2 trial demonstrated no significant differences in the efficacy, or effectiveness, of abiraterone or enzalutamide, two of the leading treatments for prostate cancer that is resistant to hormonal therapy. This research finding was consistent with most clinicians’ belief that either drug may be utilized, allowing physician and patient choice. Importantly, the study incorporated a number of interesting biomarkers using circulating tumor cell (CTC) DNA from a liquid biopsy, and the data gleaned from the DNA revealed prognostic insights about disease aggressiveness and biology. Another study showed a lack of utility to continue enzalutamide after disease progression, confirming the current practice of switching treatments after cancer growth.

Interesting data using the PARP inhibitor veliparib was presented. In a randomized phase 2 trial, the combination of veliparib and abiraterone was not better than abiraterone alone overall, but for tumors with DNA damage repair defects, there was a difference. This adds to the anticipation of results from the many ongoing randomized trials that are testing PARP inhibitors in molecularly selected patients.

Additional data was presented on genomic signatures from prostate tissue, which in combination with clinical data, are more powerful in indicating prognosis in men who receive treatment for clinically localized (low stage / early) prostate cancer.

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Dr. Himisha Beltran

Prostate cancer acquires resistance to systemic treatment as a result of tumor evolution and selection, but repeat biopsies to study how cancers evolve are challenging, invasive, and may be confounded by tumor heterogeneity. Dr. Himisha Beltran evaluated a non-invasive approach: whole exome sequencing of circulating tumor DNA in the blood. Additional data utilizing circulating tumor cell (CTC) counts as an early indicator of response may speed drug development. Clinical trials are currently evaluating measuring circulating tumor cell counts as a biomarker for whether or not treatments are working. This may be a better indicator than measuring levels of prostate specific antigen (PSA), the current indicator for response.

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Dr. Scott Tagawa presents an update on the 177Lu-PSMA-617 clinical trial for men with metastatic prostate cancer.

Dr. Scott Tagawa presented a trial-in-progress update about the clinical trial he is leading at Weill Cornell Medicine and NewYork-Presbyterian utilizing the small molecule lutetium 177Lu-PSMA-617 to target prostate-specific membrane antigen (PSMA). PSMA is a protein abundantly expressed in 85-90 percent of metastatic prostate cancer cells, and this is the first U.S. trial of its kind. Learn more about this radionuclide therapy-based clinical trial and the eligibility criteria.

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Dr. Loredana Puca

Additionally, there were many research updates presented in the area of neuroendocrine prostate cancer (NEPC), an aggressive subtype of prostate cancer that is resistant to many traditional treatment types. Dr. Loredana Puca received a Merit Award from the Conquer Cancer Foundation for her research examining the potential use of antibody-drug conjugate rovalpituzumab tesirine for treatment of NEPC. View the abstract and learn more about our open clinical trial using this antibody-drug conjugate. Dr. Himisha Beltran highlighted the significance of the loss of tumor suppressor ZFP36 in prostate cancer patients.

Prostate cancer was the first tumor type to have a cancer vaccine (sipuleucel-T) lead to longer survival, but the drug’s activity may be limited on its own. In a randomized phase 2 trial, receiving sipuleucel-T in combination with indoximod – a drug with the potential to improve immune response – kept the cancer at bay more than twice as long compared to those who received sipuleucel-T plus a placebo. This was an exciting research update showing promise for patients with prostate cancer.

New research using tumor and liquid (blood-based) biopsies demonstrated that a majority of tumors and circulating tumor cells in men with metastatic castration-resistant prostate cancer express a protein called Trop-2, justifying a targeted treatment approach. With this knowledge, we are now evaluating the safety and efficacy of IMMU-132, an immunotherapy-based drug that targets Trop-2, in an open clinical trial for men with prostate cancer.

Bladder Cancer and Other Urothelial Cancers:

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Dr. Bishoy Faltas presents on “Unlocking the Genome: Insights Into Risk and Response in Bladder Cancer” at the ASCO 2017 Clinical Science Symposium.

Dr. Bishoy Faltas was invited to present at the ASCO Clinical Science Symposium entitled “Expanding the Actionable Landscape: Bladder Cancer Genomics — Unlocking the Genome: Insights Into Risk and Response in Bladder Cancer.”

During this session, Dr. Faltas discussed the genomics of urothelial cancer, and highlighted the latest research describing new data on the frequency of inherited (germline) mutations as well as tumor (somatic) genomics and relationship to response to chemotherapy and immunotherapy. Patients with “upper tract” urothelial cancer (tumors arising in the kidney or ureter) in particular have a higher chance of harboring an inherited mutation. Different genomic alterations in the tumors may be separated into groups that are associated with better responses to chemotherapy and immunotherapy. This is becoming more clinically relevant as we can test for these genes and the number of treatment options is expanding.

Additionally, updated results of the KEYNOTE-045 study confirmed the overall survival benefit of the anti-PD1 immune checkpoint inhibitor pembrolizumab (Keytruda) compared to second-line chemotherapy in patients with prior platinum-based chemotherapy. Importantly, this was the first head-to-head trial to demonstrate the superiority of immunotherapy over chemotherapy in urothelial cancer.

Dr. Scott Tagawa contributed to the investigation of a novel oral targeted chemotherapeutic agent called RX-3117 in advanced bladder cancer patients. Learn more about our open clinical trial with RX-3117.

Kidney Cancer (Renal Cell Carcinoma):

Several different combination studies for the treatment of advanced renal cell carcinoma (RCC) were presented at the 2017 ASCO Annual Meeting. While some studies demonstrated promising response data, significant toxicity of some combinations underscored the importance of clinical trials and the recommendation to avoid combinations outside of the research setting, which is regulated and in which these types of side effects can be monitored. Several randomized phase III trials testing combination therapy are ongoing with results anticipated to lead to changes in standard of care.

Unfortunately, despite imaging that indicates no evidence of cancer metastases (spread), many patients are not cured with surgery alone. Treatment of many cancers incorporate the use of systemic (medical) therapy in addition to surgery to increase cure rates. For the most part, this strategy has not been overwhelmingly successful in the setting of renal cell carcinoma (RCC). Unfortunately, another “negative” phase III trial showed that the addition of pazopanib (Votrient) to surgery did not improve cure rates for patients with RCC. Additional data was presented utilizing either clinical or genomic biomarkers that may assist physicians in choosing patients that might benefit from the addition of the oral drugs following surgery. We continue to await the results of additional completed studies and some currently enrolling studies utilizing immunotherapy before/after surgery.

Lutetium 177 Radioimmunotherapy Clinical Trial Open for Men with Rising PSA Levels

We have an open clinical trial using radioimmunotherapy for men who have been diagnosed with prostate cancer, and whose PSAs are rising despite initial hormonal therapy but have no evidence of metastatic disease on scans (no tumors seen on CT/MRI and bone scan). This clinical trial is investigating whether attaching Lutetium 177 with the monoclonal antibody J591 (177Lu-J591) can delay or prevent the disease progression to overt metastatic disease in men with “biochemical progression”.

J591 can recognize a protein antigen known as PSMA (also known as anti-prostate-specific membrane antigen) that is present on the surface of nearly all prostate cancer tumors and circulating tumor cells.

The targeted treatment in this trial uses J591 as a delivery vehicle for the radioactive treatment (Lutetium 177) to be delivered directly to the prostate cancer cells that may be hiding or circulating in the body (for example in lymph nodes, the blood stream or the bones).

The Lutetium 177-J591 treatment approach may be ideal for men who are experiencing rising PSA levels after primary prostate cancer treatment and early hormonal therapy, but whose bone and CT scans remain negative. Even though we can’t detect the presence of cancer on these traditional imaging scans, we know from prior research that these men have what we call “micro-metastatic” disease, meaning that the prostate cancer cells are increasing throughout the body because otherwise PSA levels would not be so high or increasing at such a rapid rate. Unfortunately, even with traditional hormonal manipulation, metastases become evident in these men after months. Although we have treated many men with overt metastatic prostate cancer and demonstrated anti-tumor responses, we have also shown that we are able to target these micro-metastatic sites (tumors that are too small to be seen on CT or bone scan), and the properties of 177-Lu make it more optimal for tumors that are too small to be seen on conventional imaging.

Many patients fall in this category in a broad sense and usually these men feel completely fine. Approximately 50,000 new men per year in the U.S. suffer a biochemical relapse (rising PSA after surgery or radiation) and some of these men will have further PSA rises despite the most common type or hormonal therapy, which are injections to bring down testosterone levels. The goal is to intervene earlier on in order to bring more men to cure and suppress the disease from further progression and metastases.

Men in this phase II study will be randomized and all patients will receive oral hormonal therapy as part of treatment which also serves to boost their PSMA level (i.e. increase the number of “locks” per tumor cell). Since PSMA is the target for 177Lu-J591, radioimmunotherapy increased expression of PSMA can lead to more targeting of the otherwise invisible tumor cells. Two-thirds of patients will receive 177Lu-J591 at the highest tolerated dose that improved outcomes based on our prior study and the remaining one-third will get J591 with a diagnostic isotope (111Indium). The isotope 111-Indium (abbreviated 111In) is also an energetic radioactive particle, but it does not generally give off enough energy to kill cancer cells while still allowing researchers to take more detailed pictures of where the prostate cancer is located in the body.

Our goal is to ultimately cure the men who fall in this category by eradicating microscopic deposits of cancer, and the Weill Cornell Genitourinary Oncology team is available for patient consultations and to speak with physicians who are interested in referring patients to this trial, which is available at a number of sites across the country.

Learn more about how this treatment works in this article and video:

Promising New Radioligand Treatment for Men with Metastatic Prostate Cancer Using Lutetium 177 (177Lu)

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Using small molecules, we are able to target not only the known tumors, but can also treat the unknown tumors.

Physicians and researchers at Weill Cornell Medicine have been utilizing prostate specific membrane antigen (PSMA)-directed radioisotope therapy for more than a decade. Over the years, we have shown that we could use this approach to target the vast majority of prostate cancer tumors (“hitting” essentially all known tumors and avoiding normal organs), demonstrated anti-tumor responses when the J591 antibody is linked to a radioactive particle with a large (single) treatment, and then further improved upon this treatment (while simultaneously reducing the side effects) by dose-fractionation (splitting the dose into two).

Following our lead and with the discovery of new small molecules which also specifically bind to PSMA, European physicians have begun using these compounds tagged with the same radioactive particle. The most common molecule has been termed PSMA-617. They have shown some very nice anti-tumor responses with limited side effects. However, because European laws differ from the U.S., many men are able to pay for treatment outside of the setting of rigorous, organized clinical research studies that clearly define appropriate dosing, efficacy and toxicity.

In January 2017, research was published in the Journal of Nuclear Medicine demonstrating that Lutetium 177 combined with PSMA-617 can reduce the amount of tumors in the body and lead to remission of the cancer as measured by PSA level. Twelve German hospitals reviewed their data and compiled a publication of patients with metastatic prostate cancer who received Lutetium-177 linked to PSMA-617 (177Lu-PSMA-617). Over 18 months, 145 men whose cancer grew despite standard treatments (including abiraterone and/or enzalutamide and chemotherapy) and whose tumors “lit up” on PSMA imaging were treated. While not a proper prospective research study, they were able to determine information about both anti-tumor activity and safety. Most patients who had PSA measured before and after treatment had some decline, with 40% having PSA cut at least in half following a single treatment. Blood counts dropped in less than half (usually to moderate degrees) and some developed dry mouth and/or taste changes. Severe toxicity was rare.

It is encouraging to see that there is a treatment that might lead to reduction in cancer without severe side effects, even in men who previously have received many other lines of treatment. However, both rigorous research as well as access for our patients are current issues. Therefore, we are excited to offer a clinical trial that builds upon our prior experience of anti-PSMA radioimmunotherapy while taking into account the available European data.

This study utilizes the most commonly used molecule, 177Lu-PSMA-617, in a prospective manner. Our prior research has shown that higher doses result in significantly better anti-tumor responses, so one purpose of this study is to perform dose-escalation to determine the safest and most-effective dose without increased side effects. In addition, our research demonstrated that dose-fractionation allowed higher doses with less toxicity, so our treatment schedule will deliver the total dose in 2 fractions.

We look forward to advancing science and also making these treatments available to men in the tri-state area and across the U.S., not just those who can afford to fly to Germany for treatment. At Weill Cornell Medicine and NewYork-Presbyterian, we have an excellent, multidisciplinary team that has led the world in PSMA-targeted radionuclide therapy. We will leverage our combined expertise and experience to translate the exciting knowledge base into true clinical gains for prostate cancer patients.

To learn more about the clinical trial or enroll, click here. Call us at 646-962-2072 to make an appointment or schedule a consultation.