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.

Using Alpha and Beta Radioisotopes to Kill Cancer Cells

Radionuclides, also known as radioisotopes, are particles that emit energy. The different particles they emit vary and some types emit damaging radiation (also called ionizing particles). This is a good thing when we’re using radiation as a way to kill cancer cells. The two main categories of radiation particles used to kill cancer cells are alpha and beta particles.

Several radioisotopes – using both alpha and beta particles — have been approved by the Food and Drug Administration (FDA) for clinical use in cancer treatment. Historically, bone-seeking radioisotopes were used for patients with painful tumors in the bone. For example, Strontium-89 (Metastron) and samarium-153 (Quadramet) are beta-emitters that are taken up like calcium into bone and were approved to decrease pain. More recently, the alpha-emitting agent radium-223 (Xofigo) was approved for men with metastatic castration-resistant disease that has spread to the bone. However, unlike the previous beta-emitting agents, radium-223 was FDA-approved because it leads to longer overall survival rather than just symptom relief. Radium-223 is an alpha particle that mimics calcium and is delivered and taken up by the bone cells. This generally occurs near tumor cells, and while we don’t know the exact mechanism of action, we suspect that in addition to being in close proximity to some tumor cells, this creates a less hospitable environment for the tumor cells that have spread to the bone.

Additionally, we can now utilize different targeting agents to take radionuclides directly to the tumor cells. Radioimmunotherapy or radioligand therapy involves the practice of attaching a radioactive isotope to a cancer-targeting antibody or small molecule that binds only to a specific cancer-related molecule on a tumor cell. This is similar to a “lock and key” scenario, where the antibody or molecule resembles the key that will only recognize a very specific lock (the cancer-related molecule).

As it turns out, essentially all prostate cancer cells have a specific “lock” called prostate-specific membrane antigen (PSMA). This lock sits on the surface of each prostate cancer cell. We have engineered very specific monoclonal antibodies and molecules that will bind only to PSMA, leading to the opportunity for “molecularly targeted” (radio-)therapy.

In terms of attaching the radioactive isotopes, we can use both alpha and beta particles depending on the location and size of the tumor.Alpha vs beta radiationAlpha particles have the advantage of a very high amount of energy and a short path length. The amount of energy is high enough so that only a small number (1-10) of alpha particles lead to lethal damage to cells. An advantage of the short path length is that only the cells in close proximity to the alpha particle are destroyed, sparing other healthy and normal tissues. However, because of the short path length travelled, the alpha particle needs to be delivered into or right next to the tumor cell. In fact, even a piece of paper (or skin) is enough to block an alpha particle. Other alpha particles are being developed to be delivered as lethal payloads when attached to carrier molecules. One of these, actinium-225 (225Ac) is an alpha-emitting radionuclide that emits 4 alpha particles. In humans the 225Ac particle has been used as part of a compound linked to an antibody to treat leukemia and it also has been linked to a PSMA-recognizing peptide to treat men with late-stage prostate cancer with initial examples published last year.

Beta particles emit a lower energy, but can travel further distances. Because of their lower energy levels, more particles are required to cause lethal damage to cells.

This video provides a great overview of the process:

Additional research is needed to decipher the best radionuclides to use for which diseases in which clinical situations. We at Weill Cornell Medicine and NewYork-Presbyterian Hospital will have both alpha and beta radionuclides linked to PSMA compounds available in the clinic this year, initially with a clinical trial using 177Lu-PSMA-617, to be followed by 225Ac-J591, then the combination of 177Lu-J591 and 177Lu-PSMA-617.

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.

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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!