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.