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.

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.

beltran-attard
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!

8 Tips for a Healthy Mouth During Cancer Treatment

Four different colored toothbrushes in toothbrush holder.We grow up learning certain truths regarding the need to brush our teeth at least twice a day and visit the dentist on a regular basis, but during cancer treatment, our mouth needs can change.

Cancer treatment is designed to fight the cancer cells in your body, but in doing so can have a wide range of side effects. One of the main side effects of chemotherapy, the standard treatment for prostate, bladder, and testicular cancers, is changes that occur in the mouth. Chemotherapy can lower white blood cell, platelet, and red blood cell counts throughout the body, so patients are at increased risk for infections. Gum diseases, dental abscesses, and cavities are all infections that are prone to worsen during treatment.

While killing cancer cells, cancer treatment can also harm normal cells, such as the cells in the mouth. This can cause problems with your mucosa and gums (the soft lining of your mouth) and the glands that make saliva. Additionally, both chemotherapy and radiation treatment can cause mucositis, a side effect that involves an inflammation of the lining of the mouth and can lead to red, painful sores.

Here are 8 tips to maintain good oral hygiene and ease mouth pain during cancer treatment:

  1. Visit your dentist early in treatment. See if your doctor can identify potential sources of dental infection or irritation prior to starting chemotherapy. Get any dental cleanings, teeth extractions, and fillings at least 2 weeks before starting treatment. This will help to prevent mouth problems so that you can get the most out of your cancer treatment.
  2. Brush your teeth. During treatment, do not neglect brushing your teeth at least 3 times a day. Use a brush with soft bristles and be gentle on your gums. Consider using a toothpaste designed for sensitive teeth and gums, and make sure that your toothpaste contains fluoride to prevent cavities and tooth demineralization, especially if you have a dry mouth. If you wear dentures, make sure that they are adjusted properly with a comfortable fit. Brush and rinse your dentures after meals and do not wear them while sleeping.
  3. Keep your gums healthy. Floss regularly as long as your platelet count is above 20,000. This is to minimize inflammation of the soft tissues in your mouth which can lead to dental disease, bleeding and infection if your blood counts are low. If possible, start a good flossing routine prior to starting chemotherapy so that your gums are healthy going into treatment.
  4. Pay attention to what you eat. What you put in your mouth matters, and not just in terms of maintaining a balanced diet during treatment. Read package labels to find out what’s in the foods you’re eating, as this will help determine what may irritate your mouth. Hot and spicy sauces can increase pain and sensitivity, especially if you have sores in your mouth. Caffeinated beverages and alcohol can increase mouth dryness, and vinegars, citrus and tomato juices have a lot of acidity which can also irritate the mouth. Be in tune with which foods might be triggers, and if eating out, ask whether sauces and dressings can be omitted or served on the side.
  5. Modify your diet as needed. If your mouth is sore, eating soft, bland, room-temperature food may help. If your mouth is dry, you can add extra moisture to foods in the form of sauces, oils, milk or broth to aid in swallowing. Foods such as eggs, yogurt, cottage cheese, soups, cooked vegetables, pudding, milkshakes and smoothies can often be tolerated when your mouth is sore or dry. If you experience taste changes, experiment with different foods at different temperatures.
  6. Cut down on sugar. Avoid foods that have a lot of sugar because your teeth are more vulnerable to infections and cavities during cancer treatment. Beware of sugar content in beverages such as soda, juice, coffee, tea and sports drinks.
  7. Rinse daily with alcohol-free mouthwash. Many types of mouthwash wash contain alcohol, which can burn your mouth and contribute to oral dryness. Keep your mouth moist with an alcohol-free mouthwash. If you suffer from dry mouth, suck on sugar-free lozenges to stimulate saliva flow. Keep your lips moist with a natural lipbalm containing bees-wax or lanolin to prevent chapping or cracking. Do not use petroleum based lip balms as these can contribute to lip dryness.
  8. Know when to speak up. Be sure to reach out to your healthcare team and dentist if you’re experiencing any of the following: Swelling or pain in the mouth or jaw, trouble swallowing, mouth ulcerations that do not heal within one week, white patches in the mouth, a burning mouth sensation, or severe oral dryness.

At Weill Cornell Medicine and NewYork-Presbyterian, we provide supportive oral care before, during and after cancer treatment. To learn more about the services we offer, click here. To make an appointment with a dentist at our center who specializing in treating cancer patients, please call Dr. Heidi Hansen at 212-746-5115.

For additional information about oral care during cancer therapy, visit the below links:
  • NCI: https://www.cancer.gov/about-cancer/treatment/side-effects/mouth-throat
  • American Dental Association: http://www.mouthhealthy.org/en/az-topics/c/cancer-dental-health
  • American Academy of Oral Medicine: Information on Dry Mouth, Information on Mucositis
  • NIH (oral mucositis): https://medlineplus.gov/ency/patientinstructions/000047.htm

Special thanks to Heidi Hansen, DMD for her contributions to this article.