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.

Top Boxes_Taxynergy
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.

Best of ASCO 2016: Prostate Cancer Treatment Updates

Beltran_HeadshotLast weekend, Dr. Himisha Beltran traveled to Washington, D.C. to speak at the “Best of ASCO” meeting. She hosted the session on prostate cancer and summarized some of the most important studies presented at the 2016 American Society of Clinical Oncology (ASCO) meeting in Chicago.

She also represented Weill Cornell Medicine and NewYork-Presbyterian on a panel of the nation’s leading experts. The panel answered questions regarding some of the most challenging cases in genitourinary (GU) cancer care.

What’s new in research and treatment?

For men with advanced (metastatic) prostate cancer, the class of chemotherapy that has consistently proven to improve survival is called “taxanes.”

There are two taxanes that have been FDA-approved to treat prostate cancer, docetaxel (brand name: Taxotere) and cabazitazel (brand name: Jevtana). While these drugs are similar, men whose tumors have grown despite taking one drug often respond to the other.

Much of the important research at this year’s ASCO meeting focused on some key questions related to these two treatment options:

1. What treatment dose is best to maximize response, but minimize side effects?
2. Does the order in which patients receive these treatments matter?
3. When should oncologists switch between treatments if one is not working?
4. What is the impact on quality of life?

Another hot topic was the value and cost of treatments, and the link between treatment cost and access to care, since there can be financial barriers associated with certain treatments.

Below, we’ve outlined some of the key studies and clinical takeaways for prostate cancer treatment that Dr. Beltran discussed at the Best of ASCO meeting:

Chemotherapy Updates
  • For patients with untreated metastatic prostate cancer, large studies have recently demonstrated the improved survival impact of using a combined treatment of both chemotherapy and hormonal therapy as opposed to only hormonal therapy for men with metastatic prostate cancer. A new research study examined the CHAARTED study data and evaluated the quality of life (QOL) of patients treated on the study. This research found that while the QOL was initially worse (at 3 months), there was no long-term negative impact, and QOL was better at 12 months for chemo patients relative to those who only received hormonal therapy. This has important implications for counseling patients, as some are worried about side effects. It is comforting to know that while side effects may occur, they are temporary and the longer-term benefit of cancer control leads to improved QOL in the longer term.
Radiation Updates
  • A randomized trial examined radiation therapy for treating localized prostate cancer that had not spread beyond the prostate gland in men with intermediate risk disease. This study compared the standard eight-week course of treatment with a shorter course of four weeks, called hypofractionation. The shorter course of treatment did not see any reduction in treatment response and did not increase toxicity. The results from this study in combination with two other similar studies (RTOG 0415 and ChIPP) support using hypofractionation as a new standard for men with intermediate risk prostate cancer, as it is more convenient since it requires fewer visits to complete and is potentially less costly for patients.
Genomic Updates
  • In a large multi-institutional study of nearly 700 patients (including Weill Cornell), over 11% of patients with metastatic prostate cancer had inherited mutations in DNA repair genes (such as BRCA2 or ATM). This has important family risk and treatment implications since these genes can be passed down through the family tree and are not only linked with prostate cancer, but other cancer risk, as well. This is practice changing and supports genetic counseling and testing for all men with metastatic prostate cancer. In addition, research is ongoing to utilize drugs that may work especially well in this situation.

Dr. Scott Tagawa Presents at American Cancer Research Meeting

Dr. Tagawa
Dr. Tagawa

Weill Cornell’s Dr. Scott Tagawa presented four research posters at this year’s American Association for Cancer Research (AACR) annual meeting. Each of the presentations is summarized below. Click on the title to view the published abstracts.

 

Non-invasive measurement of prostate-specific membrane antigen (PSMA) expression with radiolabeled J591 imaging: a promising biomarker for PSMA-based radioimmunotherapy

J591 is a man-made monoclonal antibody that is able to recognize a protein antigen (PSMA) expressed on virtually all prostate cancer cells, and more so in men with treatment-resistant metastatic disease. When a tiny tag of radioactive material is attached to the J591 antibody, that specifically targets prostate cancer cells, and delivered systemically this is known as radioimmunotherapy. Dr. Tagawa has been conducting clinical trials of the precision radioimmunotherapeutic J591 to determine its ability to eradicate prostate cancer cells that have metastasized. In this poster presentation, Tagawa and colleagues performed a combined analysis of four clinical studies of this radioimmunotherapeutic that examined 130 patients with metastatic treatment-resistant prostate cancer. They found that the levels of PSMA expression—as determined by a non-invasive scan–can be used to indicate response to their radioimmunotherapy.

ERG induces taxane resistance in castration-resistant prostate cancer

Taxanes are a type of chemotherapy drug that are used to treat advanced prostate cancer; however, inevitably prostate cancer patients develop resistance to these chemotherapy drugs. In this poster, Tagawa et al demonstrate that a genetic abnormality (ERG positivity) found in half of all men with prostate cancer plays an active role in inducing resistance to taxane-based chemotherapeutics. Additionally they’ve determined that men with ERG positive tumors have upregulation of another protein (clusterin) that can cause resistance to taxane chemotherapeutics. This work dovetails nicely with Dr. Zoubeidi’s work (see above) and shows the potential to use a drug now in clinical trials (OGX-011) to enhance response to chemotherapy in men whose prostate cancer is positive for the ERG genetic aberration.

Using CTCs to interrogate mechanisms of taxane resistance in the prospective TAXYNERGY clinical trial in prostate cancer

This poster describes a prospective, randomized multi-site clinical trial that will enroll 100 men with treatment resistant prostate cancer and use advanced technology to capture and analyze cancer cells that are freely circulating in their bloodstreams. This trial will allow the researchers to look for early signs of treatment response or failure in individual cancer cells and examine the genetic and other molecular factors that indicate or lead to either a response or lack of response to chemotherapy. This is one of the few studies to utilize blood-based biomarkers in a prospective fashion. It is also a demonstration of cooperation between academic partners and the pharmaceutical industry—one that was facilitated by the Prostate Cancer Foundation.

Prostate circulating tumor cells metastasize to bone via E-selectin expressed on endothelia cells

This poster describes a molecular dance that prostate tumor cells exploit as they metastasize to bone. Understanding and characterizing the mechanisms that tumor cells use exit the bloodstream and to home to bone and set up shop should allow researchers to develop ways to interrupt the process and prevent circulating prostate cancer tumor cells from setting up cancerous shop in men’s bones.