Radiation is one of the most common treatments for prostate cancer. Using radiation, physicians are able to cure some men with cancer confined to the prostate, as well as improve symptoms for men with metastatic disease. There are many different types of radiation treatments.
One type of treatment includes injecting radioactive isotopes into the blood in order to directly reach the prostate cancer cells regardless of where they are located in the body, including the cells that have spread to the bone and other organs. For example, Radium-223 (Xofigo) is FDA-approved to treat prostate cancer that has metastasized to the bone and has been shown to improve both the quality and duration of the lives of men with advanced prostate cancer.
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).
Essentially all prostate cancers have a specific “lock” called prostate-specific membrane antigen (PSMA). This “lock” is a protein that sits on the surface of most prostate cancer cells but is absent from most other normal places in the body.
Physicians and scientists have engineered very specific “keys” in the form of monoclonal antibodies and molecules that will bind only to PSMA. When we attach radioactive particles to these keys, we are able to deliver what we call “molecularly targeted” radiotherapy.
For example, J591 is a monoclonal antibody (an engineered protein) that recognizes PSMA. Actinium-225 (225Ac) is a small radioactive particle that emits alpha-particles, a powerful form of radiation requiring fewer particles to cause damage to the cancer cells. When these are attached to one another, we call the compound 225Ac-J591 (a radioactive particle linked with a monoclonal antibody). It is designed so that J591 will recognize the PSMA on the prostate cancer cells and bring the radioactive particle 225Ac with it into prostate cancer cells wherever it goes in the body.
Our physicians and scientists are building on prior laboratory-based research presented at the 2017 Meeting for the Annual Association for Cancer Research (AACR) and are now studying the role this experimental therapy may have for men with advanced prostate cancer that has spread throughout the body. Thanks to generous support from the Prostate Cancer Foundation and the NIH SPORE award, Dr. Scott Tagawa, medical oncologist and Director of the Weill Cornell Medicine Genitourinary (GU) Oncology Program, and his team are conducting the first-ever clinical trial testing the PSMA-targeted antibody and radioactive alpha particles (225Ac-J591) for treatment of advanced prostate cancer. This promising new and unique approach has the potential to lead to another treatment option for those patients who are not experiencing the best clinical outcomes possible from standard of care therapies. Some men in Germany have received 225Ac linked to PSMA-617 with a handful of cases published with impressive responses. However, no formal studies have been performed and there are reports of bothersome dry mouth (xerostomia) and the potential for delayed kidney damage (seen in mice).
“We look forward to advancing science and also making this treatment available to men with advanced prostate cancer in the near future, says Dr. Scott Tagawa. “Our goal is to translate the existing knowledge base into true clinical gains for prostate cancer patients and it’s great that in October, 2017, we are able to treat our first patient.”
Each fall, Weill Cornell Medicine (WCM) and NewYork-Presbyterian (NYP) host a health and wellness seminar series – one seminar every week for a month – where physicians educate the local community about different types of health issues.
Last week, Dr. David Nanus, professor of medicine and urology at Weill Cornell Medicine and Dr. Scott Tagawa, medical oncologist and Director of the Weill Cornell Medicine Genitourinary (GU) Oncology Program, presented to and educated people in the local community about prostate cancer. Their presentation was titled, “Your Guide to Prostate Health and What to Know About the Leading Cancer in Men.” Following the presentation, all attendees were invited to ask the physicians questions.
Some of the key topics from Dr. Nanus and Dr. Tagawa’s presentations included the common risk factors for prostate cancer, the importance of screening, the latest treatments and research, as well as utilizing the precision medicine approach.
Key highlights from their presentations are outlined below.
Prostate Cancer Risk Factors
Prostate cancer risk factors include age, ethnicity and inherited genetic conditions. For example, those diagnosed with prostate cancer are predominantly older men. Additionally, new data points towards a surprisingly high percentage with inherited cancer genes. Those with genetic conditions such as BRCA 1 or BRCA 2 or those with prostate cancer in their family history are also more likely to be diagnosed with the disease.
Early Detection and Screening
Dr. Nanus and Dr. Tagawa highlighted the importance of screening and early detection by referencing the recently-updated National Comprehensive Cancer Network (NCCN) prostate cancer screening guidelines. Despite ongoing debate over the value of prostate cancer screening, this past September, NCCN’s guidelines suggest that screening can indeed reduce a man’s risk of dying from the disease and that prostate-specific antigen (PSA) testing and digital rectal examination (DRE) should be done. Newer tests are also available to assist in counseling about biopsies and targeted biopsies are now offered at selected centers. Dr. Scott Tagawa addressed the importance of the “shared decision-making” model when it comes to prostate cancer screening. For example, men considering screening are encouraged to discuss with their healthcare team and family members the pros and cons of getting screened and what the best course of action would be if the results lead to a diagnosis.
The presentation also addressed the different treatment approaches. As a first step, the most important factor in choosing the best way to treat prostate cancer is knowing what stage the cancer is in. Prostate cancer has been traditionally staged and “risk-stratified” based on the extent of the cancer (using T, N, and M categories) and the PSA level and Gleason score at the time of diagnosis.
We now have additional molecular tests to add prognostic value. In certain circumstances, these tests assist in the decision for “radical treatment” which has been traditionally performed with surgery and/or radiation versus active surveillance (which entails regular monitoring visits in addition to repeat imaging/biopsy). It is important to note that most men diagnosed with prostate cancer, including some that have recurrence after surgery or radiation, will never die of the disease.
Novel molecular imaging techniques have assisted in telling physicians and researchers about the location of previously unseen cancer and also providing information about the biology of certain tumors. A number of therapeutic advances have occurred over the last several years resulting in men with incurable cancer living longer with a better quality of life.
Dr. Tagawa emphasized the great strides and therapeutic advances over the years in prostate cancer treatments, but that more work still needs to be done. There are now many options for therapies that make men live longer while also making them feel better. One of the reasons for this advancement is the use of precision medicine, which means that physicians are treating each individual based on their own genetic makeup without using a “one size fits all” type of approach. A key factor in making this method successful is through clinical trials. We often interrogate a patient’s tumor from surgery or an image-guided needle biopsy. In addition, liquid biopsies are now increasingly valuable.
View this FOX 5 clip featuring Dr. David Nanus and Dr. Scott Tagawa with their patient, Alex Sarmiento, who was diagnosed with prostate cancer and tested with a liquid biopsy.
Data shows that most adults with cancer do not participate in clinical trials. It is through clinical trials that new treatments and combinations of treatments can be identified. Clinical trials pave the way toward further scientific advances that could potentially help to find a cure for prostate cancer, and other cancers as well. These trials also have the ability to offer therapies to patients that they otherwise would not have access to. The most common reason that patients do not enroll in clinical trials is because they were not told that this was an option. We suggest asking your physician about access to clinical trials at each stage of the disease and/or seeking out centers that have trials available.
Weill Cornell Medicine and NewYork-Presbyterian offers many prostate cancer-specific trials that you can search for here.
For people with advanced prostate cancer, taxane chemotherapy is the only chemo shown to improve survival. Taxanes target microtubules, which are structures in cells that are involved in cell division, as well as the trafficking of important proteins. The important androgen receptor (AR) protein is trafficked via microtubules from the cell surface into the nucleus, where it binds DNA and leads to cancer cell growth. In prostate cancer, taxane chemotherapies work in part by binding microtubules and leading to stabilization of these tracks, preventing the AR from moving into the nucleus, a novel mechanism we discovered here at Weill Cornell Medicine.
Two taxanes are approved for men with prostate cancer, docetaxel (Taxotere) and cabazitaxel (Jevtana). Docetaxel was approved for men with metastatic castration-resistant prostate cancer (mCRPC) in 2004 based upon longer overall survival and improved quality of life compared to the previous standard chemotherapy mitoxantrone (which was approved because it helped relieve cancer symptoms). Importantly, even if tumors become resistant to the first taxane used, the other can still have anti-tumor activity and lead to improved outcomes. Cabazitaxel was approved following treatment with and cancer progression during or after treatment with docetaxel in 2010 because of improved survival compared to mitoxantrone. In addition to these chemotherapy drugs, patients are usually given low-dose prednisone. While docetaxel and cabazitaxel are similar, men whose tumors have grown despite taking one drug often respond to the other. For oncologists, the challenge has been pinpointing when exactly to switch treatments.
As part of the approval of cabazitaxel, the FDA mandated that the drug maker address two questions. One question was, with two taxanes approved, is cabazitaxel better than docetaxel in controlling cancer growth? Two doses were studied in early phase clinical trials across different cancer types and the optimal dose (20 mg per body size versus the approved dose of 25 mg) was unknown. The second question was whether a lower dose (with presumably less toxicity) was as good as the full dose. In addition, our Weill Cornell Medicine team asked the scientific questions of whether switching the drugs earlier leads to better overall response rather than the traditional approach, and how can we assess the biomarkers response and resistance to the drugs?
In the current issue of the major cancer publication the Journal of Clinical Oncology, three significant studies designed to answer these questions and which highlight the impact of taxanes are published together.
The FIRSTANA trial enrolled 1168 men with chemo-naïve mCRPC, testing whether cabazitaxel administered at the standard 25 mg or lower 20 mg (per body size) dose were more effective than docetaxel (all drugs given every three weeks). The results demonstrated that cabazitaxel at either dose was not superior to docetaxel. In the first large head-to-head study, differences in side effect profiles between the drugs were highlighted. Of significance, docetaxel is available as a generic drug and is cheaper on health care systems, so it is helpful to know that we can achieve similar outcomes by starting with the more economical drug. In the current treatment era, most men receive one of the oral hormonal drugs (such as abiraterone or enzalutamide) prior to chemotherapy in the mCRPC setting, but unfortunately only a very small fraction of them were treated in this manner in the FIRSTANA study. There is some evidence that prior treatment with potent oral hormonal therapy drugs diminishes response to taxane chemotherapy and it is possible that this effect is different between the two taxanes, so this remains an open question.
PROSELICA was a study which enrolled 1200 men with mCRPC who had cancer that progressed following treatment with docetaxel. It was designed to show that a lower dose of cabazitaxel (20 mg per body size) was non-inferior to the approved dose (25 mg per body size). Half of the men received treatment with each dose. The primary endpoint of the clinical trial examined overall survival. Though there were more prostate specific antigen (PSA) reductions that lasted longer with the higher dose, overall survival was essentially the same in both groups. Additionally, there were more severe side effects with the higher dose. This trial met its endpoint of showing that the lower dose was not inferior, and a new (lower) standard dose of 20 mg per body size is now an acceptable treatment, receiving FDA approval in September 2017. Importantly, the study confirmed that the drug is effective at both doses even in men who developed resistance to the similar drug, docetaxel. Though there was a higher percentage (approximately a quarter), like in the FIRSTANA trial, only a fraction of patients were previously treated with abiraterone/enzalutamide and it is unknown how having a more contemporary group with nearly all patients receiving at least one of those drugs would affect the outcome.
In a collaborative effort between academic investigators at Weill Cornell Medicine (WCM)/NewYork-Presbyterian (NYP) and Johns Hopkins, and Pharma, the TAXYNERGY study evaluated two main questions. With the background assumption that activity between the two taxanes (docetaxel and cabazitaxel) were similar but different enough that tumors that had resistance to one drug could respond to the other, the primary clinical question was whether we could increase the response rate in the overall patient population by switching drugs if individual patients had suboptimal response initially. The randomized study was determined to be positive, with more patients achieving deeper PSA declines than compared to the prior benchmark.
Our latest research published in the Journal of Clinical Oncology also reports on updates to the TAXYNERGY trial, which showed additional evidence of using cancer cells circulating in the blood, also referred to as circulating tumor cells or CTCs, as a primary biomarker for determining chemotherapy response. This research validated prior work demonstrating the mechanism of action of taxane chemotherapy in prostate cancer. Furthermore, this research proved that with a simple blood draw or “liquid biopsy,” within one week of a patient’s first chemotherapy treatment, we’re able to determine whether men with metastatic prostate cancer are responding to therapy. If they are not optimally responding, we may be able to change treatment to the other taxane chemotherapy very early on, optimizing the likelihood of controlling the cancer’s growth by using the other, similar taxane chemotherapy. This carries great significance in that it prevents men from continuing with treatment that is not working and has associated side effects.
At Weill Cornell Medicine and NewYork-Presbyterian, when it comes to cancer care, we continue to explore new ways to improve treatment responses and provide the best clinical outcomes possible.
Additional research examining liquid biopsies in men with prostate cancer continues. In a collaborative effort funded by a Movember – Prostate Cancer Foundation (PCF) grant, CTCs are being collected before and after therapy to validate previous AR variant biomarkers and to explore additional technologies that might predict response or discover additional mechanisms of drug resistance. We continue to validate the platform of circulating tumor DNA (also called cell-free DNA) with a panel that is more specific and useful for prostate cancer than commercially available platforms.
Through a grant from the Prostate Cancer Foundation (PCF), Dr. Beltran and colleagues at WCM are working as part of an international consortium to develop, validate, and implement a ctDNA platform for prostate cancer. This targeted genomic sequencing test, called PCF SELECT, identifies tumor mutations in ctDNA from metastatic prostate cancer patients to guide treatment selection based on precision medicine. It is currently undergoing centralized development, and the long-term goal is that this ctDNA test will be widely used by the clinical prostate cancer community for precision medicine applications.