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Posts tagged ‘castration resistant prostate cancer’

TBMS Sprycel Logohe results of the phase 3 clinical trial of dasatinib (Sprycel) plus docetaxel/prednisone versus placebo and docetaxel/prednisone in men with castration-resistant metastatic prostate cancer (CRPC) are expected soon.

BMS recently updated the clinicaltrials.gov website to show that the dasatinib phase 3 randomized prostate cancer “READY” trial (NCT00744497) of 1500 men completed data collection in August.

Data is expected before year end and, If positive, could be a late breaker at the ASCO Genitourinary Cancers Symposiusm (ASCO GU) in Orlando from Feb 14-16, 2013.

Dasatinib inhibits Src-family kinases (SFK)

Dasatinib is approved for Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia and Ph+ acute lymphoblastic leukemia (ALL). It is a BCR/ABL, LYN and Src family tyrosine kinase inhibitor.

Src-family kinases (SFK) are involved with tumor proliferation and bone metabolism.

In the phase 1 & 2 clinical trials of dasatinib with docetaxel, many of the men with prostate cancer saw a decrease in PSA from baseline, reduction in tumor size and bone scan improvement and stabilization. Encouraging early results led to the start of a phase 3 randomized trial of dasatinib in combination with the chemotherapy, docetaxel.

However, the results for Src inhibitors in prostate cancer have been mixed to date, with not all agents generating positive data. Astra-Zeneca’s saracatinib (AZD0530), for example, showed little clinical effect on its own in a phase 2 prostate clinical trial.

It has been suggested by KOLs at numerous conferences that Src inhibitors may potentially be more effective in combination with other cancer agents. Data suggests that Src might be a resistance mechanism to enzalutamide (MDV3100), so it would be interesting to see whether a dasatinib/enzalutamide combination may be more effective than enzalutamide on its own.

Meanwhile, we await the data to see whether the combination of dasatinib with docetaxel generates a significant increase in overall survival over docetaxel alone. While some are “hopeful”, Dr Oliver Sartor, Professor of Cancer Research at Tulane Medical School noted in a prostate cancer session at ESMO 2012 that, “the docetaxel-combination graveyard is big!

Update Jan 26 2013: Dasatinib Phase 3 Data at ASCO GU

Results from the dasatinib phase 3 prostate cancer trial are a late breaking abstract at the 2013 ASCO Genitourinary Cancer Symposium (ASCO GU) in Orlando. The data will be presented on February 14 by John Araujo MD PhD, Assistant Professor in the Department of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston.

LBA #8: Overall survival (OS) and safety of dasatinib/docetaxel versus docetaxel in patients with metastatic castration-resistant prostate cancer (mCRPC): Results from the phase III READY trial.

2012 Annual meeting of American Association for Cancer Research in Chicago. Photo Credit: Pieter DroppertAs Sally Church, PhD noted on Pharma Strategy Blog, the 2012 annual meeting of the American Association for Cancer Research (AACR), recently held in Chicago, showcased many new cancer products in early development.

Cancer new products have a high attrition rate as they move through the development pipeline, so any promising results seen in early stages of development must be viewed with caution.

Results from laboratory studies using cell lines or trials in animals do not always translate into new drugs that work in man, e.g. they may have an unacceptable toxicity, not target the driver mutation, or adaptive resistance may just lead to the cancer bypassing the blocked pathway.

However, scientific meetings such as AACR do provide a window into the possible new drugs of the future. One prostate cancer new product that caught my attention at AACR 2012 as one to watch is AZD3514.

Sarah Loddick from AstraZeneca gave one of the few oral presentations at AACR on this exciting new compound.  This was the only AACR session I attended where I was able to access wifi. Some of my live-tweets are captured in the Storify below (click here to access this on Storify):

http://storify.com/3nt/aacr-2012-azd3514-in-prostate-cancer

Unfortunately, Sarah Loddick has not (as of time of writing) shared a copy of the AZD3514 prostate cancer poster that she presented later in the meeting, so I’m unable to write more about the preclinical prostate cancer data.

AZD3514 is a novel selective androgen receptor down-regulator (SARD) and has a different mechanism of action to drugs such as enzalutamide (MDV3100) that functionally inhibit AR signaling by binding to the AR & AR splice variants.

Sarah Loddick concluded at the end of her oral presentation that AZD3514:

  • inhibits prostate cancer growth in vitro & in vivo
  • has activity against wild-type and mutated AR
  • has activity in pre-clinical models that represent castration resistant prostate cancer (CRPC)
  • inhibits seminal vesicle growth in rats in the presence of physiological levels of circulating tumor cells.

AZD3514 is in a multi-center phase 1 clinical trial in patients with metastatic CRPC in Europe (NCT01162395) and Japan (NCT01351688). I look forward to seeing the presentation of the results from these trials.

From what I saw at AACR, AZD3514 is a new prostate cancer drug to watch.

Update April 20, 2012

I was delighted to receive an email this morning from Sarah Loddick of AstraZeneca with a copy of the AZD3514 poster that I requested (AACR abstract #3848): “Pre-clinical profile of AZD3514: a small molecule targeting androgen receptor function with a novel mechanism of action and the potential to treat castration resistant prostate cancer.

I am sensitive to the unpublished status of much of the research presented at AACR, but without giving too much away, some of the key messages from this poster are that AZD3514:

  • Binds to the androgen receptor (AR) ligand binding domain & reduces viability of prostate cancer cells in vitro. 
  • Inhibits AR transcriptional activity within 2h of exposure in LNCaP cells, and reduced both PSA & TMPRSS2 mRNA
  • Inhibits AR induced translocation to the nucleus
  • Causes AR down-regulation in prostate cells in vitro
  • Causes AR down-regulation in rat R3327H prostate tumors
  • Has activity in pre-clinical models of CRPC

A drug such as AZD3514 in prostate cancer could potentially be used to overcome resistance to enzalutamide (MDV3100), or alternatively it could be used ahead of enzalutamide if it has the potential to avoid resistance and offer better outcomes. We obviously will have to wait for clinical data to see what it’s true potential is and the data from AACR, while promising, is still only preclinical.

The prostate cancer market is a busy one and companies with AR targeted new products in development will have to offer drugs that are superior to enzalutamide if they wish to have lasting commercial success.

Update June 6, 2013: AstraZeneca terminates development of AZD3514 in Advanced Prostate Cancer

At ASCO 2013 it was announced that the development of AZD3514 in advanced prostate cancer has been terminated. You can read more about what happened in the first-in-human clinical trial in my AZD3514 blog post from ASCO 2013.

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A scientific meeting that I would have liked to have attended and one where I think attendees will obtain a lot of insight into the future of prostate cancer research is the forthcoming American Association for Cancer Research (AACR) Advances in Prostate Cancer Research meeting.

AACR Advances in Prostate Cancer Research Meeting 2012Chaired by Charles Sawyers (MSKCC) and Arul Chinnayan (Michigan) it has an impressive line-up of speakers and sessions.  The meeting takes place next week (Feb 6-9) in Orlando.

There are two presentations on cabozantib (XL184) that may offer new insights into the mechanism of action of the drug and its potential:

Cabozantinib (XL-184) and prostate cancer: Preclinical and clinical profile of a novel agent

Maha Hussain, University of Michigan Medical School, Ann Arbor, MI

Cabozantinib (XL184) inhibits androgen-sensitive and castration-resistant prostate cancer in the bone and increases bone formation in non-tumored bones
Eva Corey, University of Washington, Seattle, WA

A few of the presentations at the meeting that caught my attention include:

  • Role of inflammation (William Nelson)
  • Influence of tumor microenvironment on progression and resistance (Christopher Logothetis),
  • Novel therapeutic targets in prostate cancer (Arul Chinnaiyan)
  • Overcoming castration-resistant prostate cancer 
(Charles Sawyers)

If you have in an interest in prostate cancer research, February 6-9 in Orlando is the place to be.

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One piece of hot news at the 2011 European Multidisciplinary Cancer Congress (twitter #EMCC2011) taking place in Stockholm this weekend is the data on radium-223 chloride (Alpharadin) in metastatic castration resistant prostate cancer. The phase 3 ALSYMPCA trial results were presented in yesterday’s presidential symposia by Dr Chris Parker, Consultant Clinical Oncologist at The Royal Marsden Hospital.

Dr-Chris-Parker-Alpharadin-Presentation-Stockholm-Cancer-Congress-2011

The Scandinavian location for the presentation could not have been better, given that Alpharadin was developed by the Norwegian company Algeta. Bayer Schering Pharma AG have the worldwide commercial rights, but Algeta maintains a co-promotion option in the United States.

I first picked up on Alpharadin in a presentation given at the American Urological Association (AUA) annual meeting by Oliver Sartor (Tulane) earlier this year when he reviewed new prostate cancer products in development.

Algeta-Radium-223-Chloride-ASCO 2011-Abstract-4620At the ASCO 2011 meeting in Chicago there was a poster on the Alpharadin Phase 2 trial data (see the figure on the right) that caught my attention given that it showed an overall survival (OS) advantage.  This news was, however, largely drowned by the interest in cabozantinib (XL184).

The result is that Alpharadin has to many come out of left field. It is a promising compound for the treatment of prostate cancer that will provide new treatment options for patients with metastatic disease. In particular, use in combination with other therapies such as abiraterone acetate (Zytiga) may prolong survival to a greater extent than either does individually.

Currently, radium-223 chloride (Alpharadin) is only in investigational use and is not approved in Europe or the United States. It is, however, on the fast track towards FDA approval in 2012.

ALSYMPCA phase 3 prostate cancer data presentation ESMO ECCO 2011What makes Alpharadin exciting as a new treatment option for castration resistant prostate cancer (CRPC) is that the ALSYMPCA trial data shows that it not only provides a significant median overall survival (OS) benefit of 2.8 months compared to placebo (14 months versus 11.2 months, p=0.00185, HR 0.695), but significantly delays the time to first skeletal event by 5.2 months (13.6 months versus 8.4 months, p=0.00046, HR 0.610).

The overal survival (OS) benefit seen in the ALYSMPCA phase 3 trial is comparable to other approved agents in the post-docetaxel setting for CRPC. However, where it is unique is in the additional effect it has on skeletal related events (SRE), a common occurrence in metastatic prostate cancer.  Bone metastases are painful and have a significant impact on quality of life.

Other compounds that target the bone microenviroment such as denosumab (Xgeva), provide a delay in the time to first skeletal event in prostate cancer patients but to-date have not been shown to confer an overall survival advantage. This means that Alphardin is the first bone targeted agent to confer both an overall survival and a delay in time to first skeletal event.

After Dr Parker’s presentation of the ALSYMPCA phase 3 trial data yesterday here in Stockholm,  Professor Wim Oyen of the Department of Nuclear Medicine in Nijmegen discussed the data.

What he noted was the high tolerability of Ra-223 chloride (Alpharadin) as compared to other radiopharmaceuticals for treatment of patients with bone metastases.  He discussed how the emission of alpha particles allows for a short range effect (a few cell diameters) that is very localized, but with a large biological effect.

Oyen highlighted the “opportunity for improving patient outcome by adding Ra-223 in regimens of combination therapy,” something that Dr Parker speculated about in his media briefing.

Professor Oyen also saw “an opportunity for improving patient outcome by using Ra-223 in an adjuvant setting.”  His conclusion based on the phase 3 ALSYMPCA trial data presented was that radium-223 chloride (Alpharadin) is an “effective, very well tolerated and convenient treatment modality.

Algeta-radium-223-chloride-alpharadin

Dr Parker mentioned to me, while waiting for a train back to Stockholm, that the ALSYMPCA trial data he presented had not yet been submitted for publication. He said he would be disappointed if it did not appear in the New England Journal of Medicine. Given that it is groundbreaking and “practice changing,” I would be surprised if it is not published in the NEJM in due course.

I am sure that we will be hearing more about radium-223 chloride (Alpharadin) in the forthcoming months, especially now it is on fast track to FDA approval in 2012.

Although not a cure for prostate cancer, the ALSYMPCA trial data presented here in Stockholm is further good news for patients, and will provide a potential new treatment option for urologists and oncologists.

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Earlier this week Bayer & Algeta announced that Alpharadin™ (radium-223 chloride) had received Fast Track designation from the FDA for the treatment of castration-resistant prostate cancer (CRPC).

Bayer signed an agreement with Norwegian based Algeta in 2009 for the global commercial rights to Alpharadin™, with Algeta retaining a 50/50 co-promotion and profit-sharing in the United States.

According to the Algeta August 23, 2011 press release, in light of the FDA fast track designation they plan on filing for United States approval in mid-2012, ahead of previous expectations.

At the ASCO annual meeting in Chicago this year, phase II clinical trial data for Alpharadin™ was presented during the poster session (Abstract #4620).  You can obtain a copy of the poster here.

ASCO Alpharadin™ Phase 2 Data showed increase in Overall Survival

What impressed me when I saw the poster and talked to Gillies O’Brien-Tear, the Chief Medical Officer for Algeta, was the increase in overall survival (OS) seen. In the phase 2 study presented, Alpharadin™ improved OS by 4.5 months versus placebo when added to the standard of care in patients with CRPC and bone metastases.

To me this stands out from other drugs that are targeting bone metastases in CRPC, such as cabozantinib (XL184) and denosumab (Xgeva®), where to my knowledge no overall survival benefits have yet been seen.

Despite the lack of OS benefit, Amgen announced earlier this week on Aug 22nd, they had made a supplemental BLA application for denosumab to expand the indication to include the prevention of bone metastases in CRPC. The PDUFA date is April 12, 2012.

Will Xgeva® and Alpharadin™ be viewed as potential competitors or used synergistically? It will be interesting to see any data that shows the impact of Alpharadin™ on bone pain and quality of life, and how physicians view the new treatment options that may be available to them.

How does Radium-223 chloride act? 

It is a calcium mimetic that is taken up by bone, where the radium then emits alpha-particles that act on the prostate cancer bone metastases.  The radiation is only short range (2-10 cell diameters) which limits its toxicity to healthy tissue and results in localized and focused radiation that kills metastatic cancer cells in the bone.

The day after the phase 2 results were presented at ASCO, Algeta and Bayer announced on June 6, positive data from the interim analysis of the phase 3 ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer patients) trial.

This study began in June 2008, with enrollment of 922 patients completed in January 2011. According to the June 6 press release, the interim analysis of the ALSYMPCA trial showed a statistically significant increase in overall survival in CRPC patients receiving Alpharadin™ compared to placebo.

Median overall survival was 14.0 months for Alpharadin™ and 11.2 months for placebo (two-sided p-value = 0.0022, HR = 0.699)

As a result of the interim analysis, the independent data monitoring committee recommended that the trial be stopped and patients on the placebo arm offered treatment with Alpharadin™. Dr Chris Parker, from the Royal Marsden Hospital, and Principal Investigator of ALSYMPCA, said:  

“Based on the observed survival benefit and its safety profile, Alpharadin may become an important treatment for patients with bone metastases from advanced prostate cancer.”

At the forthcoming European Multidisciplinary Cancer Congress in Stockholm (co-sponsored by ECCO, ESMO and ESTRO), the phase III Alpharadin data for the ALSYMPCA trial will be presented as a late breaking abstract on September 24, 2011 in the Presidential Session.

The abstracts for the meeting are not yet available, but in the light of the FDA Fast Track designation earlier this week, and the fact the ALSYMPCA trial results will be presented in a plenary session at Stockholm, positive data is expected.

The prostate cancer market is certainly heating up with the approval earlier this year of Zytiga™ (abiraterone acetate) and several products in late stage development such as Alpharadin™, MDV3100, TAK-700 and custirsen (OGX-011). It’s good news for patients that new treatment options may be available before too long.  As to how these new therapies are used, sequenced and combined, that is set to be the topic of conversation at medical and scientific meetings over the coming year.

Launch of Zytiga (abiraterone acetate) at 2011 annual meeting of American Urological Association (AUA) in Washington DCThe market for prostate cancer therapies is set to expand from $1 billion currently to $5 billion by 2015, according to analysts reported by this morning’s Washington Post/Bloomberg news.  This is perhaps no surprise given the recent approval of abiraterone acetate (Zytiga®) from Ortho Biotech (JNJ).

New clinical data on prostate cancer clinical trial results is expected at the 2011 annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago this weekend from many of the prostate cancer therapies in development such as MDV3100, TAK700, ARN-509, cabozantinib (XL184), ipilimumab, custirsen (OGX-11), BPX-101, alpharadin, denosumab (Xgeva®) and Prostvac-VF.

Indeed, one could argue that prostate cancer is becoming a competitive marketplace.  Any emerging biotechnology company that is not already developing a prostate cancer drug is likely to find it a hard market in which to create a blockbuster.  By the time any drug comes to market, there will be incumbents with effective products who have captured market share.

Prostate cancer is an exciting market to watch from a marketing strategy and patient perspective, as several companies potentially bring new products to market over the next few years.

However, the bottom line is that patients will live longer as a result of all the innovation that is taking place.  Not only that but physician education and awareness of how to treat this disease is also likely to improve as they seek out knowledge on new therapies and treatments.  This to many will make a major difference.  At the recent American Urological Association (AUA) annual meeting, the sessions on treatment of prostate cancer were standing room only.  There is clearly a demand for knowledge out there as the treatment paradigms change.

At the other end of the spectrum, there is also innovation taking place in terms of improved diagnosis and treatment of prostate cancer.  Whether we should screen all men for PSA remains a controversial topic, although use of risk calculators do appear to offer less false positives.  Indeed, calculating risk is going to be one of the key areas that primary care physicians and urologists need to focus on, particularly in the light of the PIVOT trial data that was presented at AUA, showing radical prostatectomy (with risks including incontinence and erectile dysfunction) was not better than watchful waiting in low-risk, early stage disease.

However, a presentation I am looking forward to at ASCO 2011 is on circulating tumor cells (CTC) and whether these can be a prognostic or even a predictive biomarker.   Both the phase III MDV3100 and abiraterone acetate clinical trials captured CTC data.  It will be exciting news at ASCO 2011 if circulating tumor cells that require only a blood sample offer an improvement over PSA not only for detection of prostate cancer, but in monitoring the disease over time.

I will be at ASCO 2011 this weekend, and look forward to writing more on prostate cancer from the conference!

One of the sessions that I attended at the 2011 annual meeting of the American Urological Association (AUA) focused on research into advanced prostate cancer.  A particularly thought provoking presentation was:

Time trends of biochemical recurrence (BCR) following radical prostatectomy (RP) among 1574 BCR patients (Abstract #639)

Presented by Alex Haese from Hamburg, Germany, this paper was a retrospective analysis of 1,574 patients who had a biochemical recurrence (PSA > 0.2 mg/dl) following RP. Researchers looked at clinical progression and cancer specific survival rates and compared their findings to published United States data.

The results appeared to be somewhat depressing for European patients who experience a BCR, with a time to BCR of 1.8 years, compared to 2.1 years in the US research by Pound from Johns Hopkins and 2.4 years in the data published by Hull, at Memorial Sloan Kettering Cancer Center (MSKCC).

Once a BCR is experienced, the time to metastases is faster in Europe, 4.7 years in the research presented by Haese at AUA, as compared to 8 years in US research by Pound. Risk factors for metastasis free survival include time to BCR i.e.

“The longer the interval between RP and BCR, the greater the probability of being met-free.”

In other words delaying time to progression is associated with longer survival.

Following BCR, time to Prostate Cancer death was 6.0 years in the 1,574 European patients, compared to 13 years in the US Pound research.  Again, the data presented showed that,

“The longer the interval between RP and BCR, the greater the probability of being alive.”

This research must be put into context, as metastasis and death in BCR patients are rare (92% of the 1,574 patients with BCR were free of metastases at 5 years, 81% at 10 years).  However, for those patients who did progress, the results appear significantly different between the US and Europe.

What could explain this?

The presentation left this question unanswered, although in Q&A it was briefly touched upon. One person raised the question of whether differences in screening could be the difference in Europe vs. US?

Other questions that come to mind are whether the subject populations in the Hull and Pound data were comparable.  The German data also had more patients (1574) compared to 304 in the Pound research and 147 (Hull) raising the question that the larger sample size may be more accurate data?

Other factors that might possibly explain the difference include:

  • Androgen deprivation therapy (ADT)
  • Radiotherapy
  • Supportive care (eg bisphosphonates)

All of which tend to be more aggressively pursued as treatment options in the USA.

Overall, this presentation raised the interesting question of US/European differences in Prostate Cancer progression that hopefully will be answered by future research.

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