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.

ESMO: Day 3 Recap

At ESMO 2017, Sunday, September 10th was the day with the largest number of genitourinary (GU) cancer presentations, including two kidney cancer and urothelial cancer highlights in the Presidential Symposium, many poster presentations, and two poster discussion sessions. We’ve broken down the full day of research updates by cancer type.

Kidney Cancer

ESMO_CheckMate 214In the Presidential Presentation on kidney cancer, results were presented from the CheckMate-214 trial. Nivolumab is an anti-PD1 antibody approved for patients with advanced renal cell carcinoma (RCC) previously treated with a VEGF-targeted therapy based upon a randomized trial demonstrating an overall survival benefit. The combination of using immune checkpoint inhibitors transitioned from laboratory science to safety studies to full approval in melanoma based upon randomized trials. The CheckMate 214 study tested the efficacy of the combination of nivolumab plus ipilimumab versus one of the most standard VEGF multikinase inhibitors, sunitinib, in previously untreated patients with advanced RCC. The study focused on the intermediate/poor risk population, but also enrolled patients with good risk disease. The study met its endpoints in an impressive fashion. In the target intermediate/poor risk population, the immune checkpoint inhibitor combination led to an improved response rate and overall survival benefit versus the active drug sunitinib. Nine percent of patients had a “complete response” with the combination immunotherapy (meaning complete disappearance of all evidence of cancer on scans). In addition, the entire patient population (with patients in all prognostic groups combined) experienced an improvement in both response and overall survival with immunotherapy.  There were some interesting exploratory analyses of subgroups and the PD-L1 expression status that will lead to additional investigation, but the study will lead to a paradigm shift and create a new standard of care for patients with advanced RCC.

In the Alliance-led A031203 “CaboSun” study, patients with intermediate and poor-risk advanced renal cell carcinoma (RCC) were randomized to receive either cabozantinib or sunitinib. The initial results of the study as assessed by the investigative team showed a benefit of cabozantinib over sunitinib in terms of the trial’s primary endpoint of overall survival. One previous caveat of the study was that interpretation of scans by investigators who are also the treating physicians can be biased. An updated analysis added independent review of scans as well as longer follow up. The progression-free survival benefit of cabozantinib was confirmed by independent review and the magnitude of benefit was increased with longer follow up.

Approximately a third of patients with advanced RCC have bone metastases and this may be a negative indicator of prognosis (also known as a “negative prognostic factor”). Radium-223 is an FDA approved agent for men with metastatic castration-resistant prostate cancer and predominant bone metastases that has been shown to benefit overall survival. A team of investigators from Boston assessed whether adding radium-223 to standard sunitinib or pazopanib would also benefit patients with kidney cancer. The combined treatment was determined to be safe and and markers in the blood and urine indicating that the bone is breaking down – a measure of bone metastases – improved with treatment. Additional randomized trials are needed to assess the true effect of this combination on overall survival.

Bladder and Urothelial Cancer

ESMO_RANGEDuring the ESMO Presidential Presentation on urothelial cancer, results from the RANGE clinical trial were presented. The utility of chemotherapy is limited in patients with advanced urothelial carcinoma whose cancer has progressed after initial platinum-based chemotherapy. Ramicurimab is a monoclonal antibody against the angiogenic factor receptor VEGF-R2. We performed a randomized phase II trial pointing towards a response and progression-free survival benefit with the addition of ramicurimab to docetaxel chemotherapy in this patient population. The RANGE study is a phase III study in which patients with advanced platinum-resistant urothelial carcinoma, with or without treatment with an immune checkpoint inhibitor, were randomized to docetaxel with ramicurimab or placebo. This phase III trial confirmed the benefit of ramicurimab when added to docetaxel in improving progression-free survival and response rate. In addition, there was no significant additional toxicity with the combination, also referred to as a doublet. We await the final overall survival results and additional analyses to assess the place of this combination in our growing treatment armamentarium for urothelial carcinoma.

Several studies examined the genetic material (genome) of tumors in patients with urothelial carcinoma. In a large clinical trial including more than 2000 patients with advanced urothelial carcinoma, investigators utilized the FoundationOne platform to assess the tumor genome of a mix of primary and metastatic tumors arising from the bladder, renal pelvis, and ureters. The study described the landscape of this disease using the targeted sequencing platform, showing a relationship between some common alterations (such as genes for Her2 and PI3K) and a higher rate of overall mutations or “tumor mutational burden” (also referred to as “TMB”).  An analysis of the Checkmate-275 study which led to the approval of nivolumab in patients with progressive urothelial carcinoma after chemotherapy looked at tumor mutational burden and survival outcomes. Higher tumor mutational burden was associated with both better response and survival in patients treated with nivolumab, a form of immunotherapy called an anti-PD1 checkpoint inhibitor. This result was independent of PDL1 status – a specific measure of this a type of mutational burden–  but perhaps stronger in PDL1 low tumors.

Dr. Scott Tagawa, Medical Director of the WCM/NYP Genitourinary Oncology Program, presented a research update regarding patients with advanced urothelial carcinoma who were treated with sacituzumab govitecan (IMMU-132)  after prior chemotherapy. This drug, which links an antibody against Trop2 (which is usually present to a high degree in urothelial carcinoma compared to normal cells) to a potent chemotherapy metabolite, was administered to 41 patients with cancer progression despite an average of three prior treatment regimens. Significant tumor shrinkage (i.e. partial or complete responses) occurred in 34% of patients. In addition, median progression free survival of approximately 7 months and overall survival of approximately 16 months was impressive compared to the expected rates for this patient population.

Prostate Cancer

Prior prostate cancer research has demonstrated strong links within family trees, and as a result, there has been a large push for research to identify where exactly in the genetic profile this risk comes from and whether these genes are passed down through ancestry. In the UK Genetic Prostate Cancer Study (UKGPCS), investigators performed a case-control study of men with and without germline (inherited) DNA damage response and repair genes (those responsible for repairing the DNA of cells in the body) identified in their 167 gene panel. Like in other studies, those with germline alterations had worse cancer-specific outcomes and overall survival rates. Notably across studies, the presence of these inherited genes is not limited to men diagnosed at an early age, so a discussion with physicians about the risks/benefits of genetic testing should be considered.

Our collaborator Dr. Armstrong of Duke University presented research analyzing PSA changes in the PREVAIL trial which led to the FDA-label expansion of enzalutamide for men with mCRPC and no prior chemotherapy. As he and others have previously demonstrated with other drugs such as docetaxel and abiraterone, a lack of PSA decline while on treatment was associated with a poor outcome.

ESMO_ValeTwo presentations focused on men with hormone-sensitive high risk and advanced prostate cancer.

Dr. CL Vale from the UK presented an analysis of data available from randomized trials which pointed towards abiraterone + androgen deprivation therapy (ADT) having a large early relative survival benefit of 37% after 3 years, and docetaxel + ADT having a smaller, but still large and significant 23% survival impact after additional follow up for 4 years.

In prostate cancer, there is a “TNM” staging system that indicates the size range of the primary tumor (T), whether the cancer has spread to the lymph nodes (N), whether there are signs that the cancer is metastatic and has spread elsewhere in the body (M). When there are no signs of distant metastases, the corresponding staging is “M0” which translates to M zero, or no metastases. ESMO_M0_ProstateCancer

Dr. Nicholas James from the UK presented data on the “M0” population of 915 men without distant metastatic disease receiving abiraterone + ADT versus ADT with or without radiation as part of the STAMPEDE study. In the overall group with M0 disease, so far there have not yet been any detectable differences in survival, which is not surprising since this subset of men tend to live for a long time while on therapy. There were though, important improvements in the amount of time to cancer growth or the development of metastatic disease. In those men with clinically evident lymph node metastases at diagnosis (corresponding to the symbol “N”), the combination of all three treatments — abiraterone, ADT, and radiation — demonstrated a significantly better survival benefit than those treated with ADT + radiation, which was in turn better than ADT alone.

Additionally, new information on interesting early phase clinical trials was also presented at ESMO.

At Weill Cornell Medicine and NewYork-Presbyterian, we participated in a clinical trial utilizing INO-5150, a DNA vaccine against PSA and PSMA. This vaccine was administered with electroporation (essentially a small electric shock at the injection site) and with or without INO-9012 (an IL-12 vaccine) designed as an adjuvant treatment to improve immune responses to the INO-5150 treatment. Men who received either one or both vaccines had few side effects other than skin reactions at the injection site and many developed immune responses. Additional study is warranted to test anti-tumor efficacy.

EC1169 is comprised of a small molecule PSMA ligand linked to a tubulysin drug. Updated data were presented in this trial where men with metastatic castration resistant prostate cancer (mCRPC) who had both received and not received prior chemotherapy were treated with EC1169. As more men were treated on trial, researchers were able to document safety and tolerability of the drug, while demonstrating the drug’s ability to control the cancer, particularly in men who had previously received docetaxel chemotherapy.

In prostate cancer, one of the mechanisms of resistance to hormonal therapy is activation of the PI3K/AKT pathway. GSK2636771 is a PI3K inhibitor that was tested in a phase I study by adding the drug to enzalutamide in men with mCRPC who had experienced some cancer progression while taking enzalutamide alone. Importantly, the trial demonstrated that GSK2636771 was safe and a signal of efficacy was present in the small trial. Additional studies are planned which will be adding the drug to enzalutamide to truly test its ability to control cancer growth. Of note, the PI3K pathway is indicated in the formation and growth of numerous cancers and was discovered by our cancer center director, Lewis Cantley, PhD.

Check out our prior ESMO 2017 Day 1 and Day 2 Recaps.

ESMO 2017: Day 2 Recap

IMG_3948The second day of ESMO included the oral genitourinary (GU) oncology session that focused on renal cell (kidney) and urothelial (bladder) carcinoma.

Several years ago, the SWITCH study evaluated the sequence of sunitinib and sorafenib showing similar overall progression free survival and overall survival regardless of the order by which each drug was utilized. At ESMO 2017, results of the SWITCH-II trial were presented. This study tested the sequence of pazopanib and sorafenib in patients with advanced RCC of any histology (i.e. clear cell or non-clear cell).  The study sought to enroll 544 patients, but stopped after 377 patients due to slow accrual. Only half of the patients remained on study and switched to their assigned drug after tumor growth on drug #1. Overall, while the study didn’t complete planned accrual, there was a trend for improved progression-free and overall survival for the pazopanib → sorafenib sequence.

Historically when most patients were treated with cytokines (IL-2 and interferon), two randomized trials by U.S. and European cooperative groups showed that in the setting of metastatic kidney disease, patients live longer by first removing the kidney mass and then treating with interferon rather than treating with interferon without removal of the kidney. Since the introduction of new therapies in late 2005 which have higher rates of tumor shrinkage and longer lifespans for patients, it is unknown if patients should still have their kidney tumor removed prior to drug therapy.

IMG_3954In the EORTC 30073 SURTIME trial, European investigators decided to try to assess whether tumors remained under control longer and patients lived longer if surgery was performed first or if patients initiated sunitinib for 3 cycles prior to cytoreductive nephrectomy. Because enrollment was slow, the study design was changed to assess the percent of patients that were free of tumor progression at 28 weeks. Ninety-nine patients were randomized to immediate versus delayed surgery, most with large kidney tumors and intermediate-risk cancer. Overall there was no difference in the percent with cancer progression at 28 weeks with either approach.  With the caveat of a small study, there were trends for longer survival and less surgical complications in those with delayed surgery. While the amended study is not able to prove that delayed surgery is the better approach, it gives comfort for those physicians/patients that the choice to initiate medical therapy and then re-evaluate for surgery is acceptable. We await the results of the larger CARMENA study that is testing surgery followed by drug versus drug alone (with no surgery) to see if removal of the primary kidney tumor is necessary.

Additionally, two early-phase studies of novel drug combinations of immunotherapy + targeted therapy were presented. In a phase I study led by the NCI, the safety of the combinations of cabozantinib/nivolumab and cabozantinib/nivolumab/ipilimumab were tested in patients with a number of different treatment-refractory tumor types, especially urothelial and other types of bladder cancers. Overall, both combinations were deemed to be safe and are moving forward in a phase III trial. However, many toxicities did occur and most patients needed to reduce the dose of at least one drug so these combinations should only be used in a clinical trial setting.

IMG_3958The phase II portion of a phase I/II study testing the combination of lenvatinib + pembrolizumab. The initial (phase 1) portion of the study presented at ESMO 2016 determined the safe dose in patients with different types of tumors (mostly RCC). This year, new results were presented with 22 additional patients added to the 8 previously treated on the phase I portion. Overall, there was an impressive tumor response rate of 63%, with 83% significant tumor shrinkage in those patients treated in the 1st line setting. This combination is also being tested in a phase III study for patients with advanced RCC which will soon be opening at Weill Cornell Medicine and NewYork-Presbyterian.

Missed our Day 1 Recap of ESMO 2017? Check it out here.