Treating Prostate Cancer with Taxane Therapies: What the Latest Research Shows

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.

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In the photos from a sub-optimally responding patient on the right, almost all of the androgen receptor (AR, labeled in green) is in the nucleus (indicated by the arrow which is overlayed in blue on the right), meaning that the taxane chemotherapy treatment was unable to block AR from moving to the nucleus and thus unable to kill the prostate cancer cells.

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.

6 Myths About Chemotherapy

Scott Tagawa, M.D.

dr-scott-tagawaChemotherapy often gets a bad rap due to the perception that the side effects of this cancer treatment are severe. What many people don’t know is chemotherapy refers to an umbrella category for different medications that work in a similar way. Just as different cancers are unique, chemotherapies are also unique and use different formula compounds. They also have brand and generic names.

I want to dispel some of the things I hear from patients about chemotherapy. Here are 6 of the most common chemo myths and misconceptions:

  1. It doesn’t work. False! While new cancer treatments are continuously being researched and developed, chemo remains the treatment gold standard for many types of cancers – including testicular cancer and metastatic prostate and bladder cancers – because it works. Through rigorous research, chemo has been shown to improve survival and increase the cure rates for many cancers, especially genitourinary (GU) cancers. Testicular cancer now has an approximately 99% cure rate which was not possible before chemotherapy. Additionally, chemotherapy increases the cure rates for bladder cancer and was more recently shown to have one of the most significant increases in survival compared to any other prior therapy for prostate cancer. Unfortunately, chemo doesn’t always work on every single type of cancer. In addition to the development of novel therapies, work is ongoing to help us select patients that will have more or less benefit from chemotherapy.
  2. It has significant side effects. This is partially true depending on what type of chemo you’re taking and what you perceive to be a negative side effect. Some chemotherapies cause hair loss as they attack the cancer cells, and this is one of the most “visible” side effects of treatment. What many people don’t realize, however, is that chemo can make patients feel better almost immediately because of its ability to control the cancer. For example, the first chemotherapy approved for prostate cancer (mitoxantrone) was approved because it made men feel better. The next generation chemotherapy (docetaxel) made men feel even better when compared to mitoxantrone. Moreover, the impact chemo has on quality of life is often short-term. Longer term, patients who undergo chemo report feeling better. A recently presented study showed that while overall quality of life was worse at an early time point during chemotherapy, men with metastatic prostate cancer had a superior quality of life a year later. This is likely due to the combination of better long-term cancer control and the fact that most chemo-related side effects are temporary. Additionally, while new treatment options, including immunotherapies, hold promise for many types of cancers, these do not work for everyone and are not without side effects either.
  3. It isn’t a one-size-fits-all approach. There are over 200 types of chemotherapies, each differing in function and specific use. For example, platinum-based chemotherapies are mainly used for bladder cancers while taxanes are used for prostate cancer.
  4. It isn’t a targeted treatment. Chemo is targeted in certain ways because it acts on specific receptors. For example, taxanes, which are one type of chemotherapy agent, have the ability to stop cells from growing by targeting structures inside the cell that help it multiply. In prostate cancer specifically, taxanes kill cancer cells by blocking the movement of specific receptors that promote cancer growth. At Weill Cornell Medicine and NewYork-Presbyterian, we are able to analyze the tumor for genomic mutations that can tell us whether you are more or less likely to respond to this type of treatment.
  5. It is painful. When you are receiving cycles of chemotherapy, it should not hurt. Some patients receive chemo through an IV (intravenously), while other chemos are given as oral medications that you can take at home. Most genitourinary cancer patients undergo treatment on an outpatient basis. If you experience discomfort, burning, or coolness speak to your nurse or another member of your cancer healthcare team.
  6. Chemo suppresses the immune system. I commonly hear this from patients as a reason to avoid chemo. While there is an infection risk associated with chemotherapy if blood counts are low, current data indicates that combining chemo with immunotherapy (either together or sequentially with one followed by the other) may be better than immunotherapy alone.

Oncologists and researchers are always looking for the best treatment options to bring cures to the greatest number of cancer patients. For many patients, chemo remains the best option at controlling the cancer growth and ultimately curing the cancer. For some patients, newer approaches such as immunotherapy or other biologic agents are more tailored to fighting their disease. At Weill Cornell Medicine, we continue to work on identifying which chemotherapy is best for the right tumor in the right patient at the right time, as well as developing strategies to deliver chemotherapy preferentially to tumors (sparing normal organs), and continuing to develop new immunotherapies and biologic-based approaches to treatment.

Chemo and Prostate Cancer: Not All Treatments (or Cancers) are Created Equal

By Scott Tagawa, M.D.

In casual conversations, chemotherapy is often referred to as one type of cancer treatment, but it actually refers to different classes of drugs/medications that work via a similar mechanism.

Taxanes are the only class of cheTagawa_Prostate Cancer_Chemotherapymotherapy agents that have significantly improved survival in men with advanced prostate cancer. These include docetaxel (Taxotere ®) and cabazitaxel (Jevtana ®). Though there have been exciting advances in hormonal therapies, bone-targeted therapies, and immunotherapies that have led to a multitude of FDA-approved therapies for patients, chemotherapy is a mainstay.

Chemotherapy was initially approved because men with advanced prostate cancer felt better and in less pain after receiving it. In 2004, docetaxel chemotherapy was approved because it made men feel even better than the older chemotherapy and it also controlled the prostate cancer well enough to lead to longer lifespan. However, the use of chemotherapy was initially limited due to fears of side effects and since 2011, additional medicines have been approved.

The recent success in large clinical trials using taxane chemotherapy has demonstrated unprecedented survival advantages when these drugs are used early. The CHAARTED and STAMPEDE trials showed a much larger improvement in survival compared to any treatment that has been studied in the modern era. Additional trials of men with earlier stages of prostate cancer have also pointed towards patient benefit. However, not all men respond to this treatment and despite improvements in quality of life for symptomatic men with advanced cancer, side-effects do exist. As a result, there is interest in identifying markers that can more accurately identify patients who will respond to this treatment and those for whom taxane chemotherapy is less likely to work. Many efforts are already in the works and progress has already been made.

A genetic alteration known as TMPRSS2-ERG that was co-discovered by Weill Cornell Medicine (WCM)’s Dr. Mark Rubin, Director of the Caryl and Israel Englander Institute for Precision Medicine, is unique to prostate cancer and present in tumors in about 50% of men with prostate cancer. Interestingly, we later discovered that the protein created by this gene fusion called ERG binds to tubulin, which is the molecular target of taxane chemotherapy.

Because of this protein’s interaction with tubulin, there is interference with the “drug-target engagement” of taxanes, leading to resistance. With this scientific discovery, in addition to outlining the mechanism and demonstrating drug-resistance in lab experiments, WCM investigators in collaboration with a group in Sydney tested tumors from human patients that received docetaxel chemotherapy. In this small group of men, those whose tumors expressed ERG were less likely to respond to docetaxel.

In a recent publication, Spanish investigators built on this discovery and identified TMPRSS2-ERG as a biomarker present in the bloodstream, making it a potentially easy way to use a blood test to predict resistance to taxane chemotherapy. This group of scientists from Barcelona used a blood test in men with advanced prostate cancer prior to starting docetaxel or cabazitaxel chemotherapy to determine the presence of TMPRSS2-ERG. Their work confirmed that men with tumors harbouring the gene fusion have resistance to this type of chemotherapy.

Though additional research is ongoing (and needed), there are now a number of treatment choices available. In the near future, physicians might be able to pick the drug that is most likely to work on an individualized basis, perhaps even through a simple blood test. This is another step towards our goal of precision medicine: the right treatment for the right patient at the right time.