PIVOT data continues to show no survival benefit for prostatectomy over watchful waiting in men with low to medium risk early prostate cancer

Timothy J. Wilt MD, MPH presented an update on the VA, NCI, AHRQ Prostate cancer Intervention Versus Observation Trial (PIVOT) on the final day of the 2012 European Association of Urology (EAU) Congress in Paris.

I previously wrote on this blog about the PIVOT data presented by Professor Wilt in the plenary session at the 2011 American Urological Association Annual meeting.

The PIVOT trial objective according to Dr Wilt, was to answer the following question:

Among men with clinically localized prostate cancer detected during the early PSA era, does the intent to treat with radical prostectomy reduce all-cause & prostate cancer mortality compared to observation?

PIVOT enrolled 731 men from 1994 to 2002 who were randomized to either receive radical prostatectomy or undergo just observation.

The results from the trial provide level 1 evidence based medicine (highest standard) concerning the survival benefits conferred by radical prostactectomy (with the potential for quality of life impacts such as incontinence & erectile dysfunction), as compared to not undertaking surgery, but instead doing observation only in the form of watchful waiting or active monitoring.

Dr Wilt told the urologists in the EAU 2012 Congress plenary session, that after a median follow-up of 10 years (interquartile range = 7.3 to 12.6), the median survival was 12.7 years. Wilt told the audience that:

“Prostate cancer mortality was uncommon occurring in only 7.1% of men, it did not vary considerably by patient age, race, comorbidities or health status, but did vary considerably by tumor risk status ranging from 3 % in men with low risk disease to 13 % in men with high risk disease.”

PIVOT Prostate Cancer Mortality Results

No of Deaths: 52/731 (7.1%)

Low risk (3.4%)
High risk (8.4%)
High risk (13.3%)

In the men who had death judged to be due to prostate cancer, “absolute differences between treatments were less than 1%,” Wilt said.

As far as I could determine, the data presented at EAU 2012 was no different from the PIVOT data presented at AUA 2011 other than being another year mature.

A subgroup analysis showed that surgery conferred no survival benefit over watchful waiting except for high-risk patients. In his EAU 2012 presentation, Dr Wilt described the subgroup findings in more detail (emphasis added):

Low Risk Prostate Cancer

“In men with low risk prostate cancer, disease mortality occurred in less than 3% and did not differ between radical prostatectomy and observation” (HR=1.48; ARR=1.4, P=0.54). This favored observation.”

High Risk Prostate Cancer

“Among men with high risk tumors, prostate cancer mortality occurred in approximately 13%. Radical prostatectomy produced a 60% relative risk reduction (HR = 0.4, ARR = 8.4) of borderline significance (P=0.04).

Intermediate Risk Prostate Cancer

“Among men with intermediate risk prostate cancer, we found a non-significant reduction of 4.6%.”

PSA <= 10ng/ml

“In men with PSA <= 10ng/ml there was no significant difference between radical prostatectomy and watchful waiting.” (HR = 0.92, ARR=0.3%, P=0.82). The findings were virtually identical throughout the course of the study. The lines are essentially superimposable for prostate cancer mortality in men treated with observation or with radical prostatectomy.”

PSA > 10ng/ml

“Among men with baseline PSA > 10ng/ml, radical prostatectomy reduced prostate cancer death by a relative 64% and an absolute difference of 7.2%. You can see the curves begin to separate at approximately 7 years.” (HR=0.36, ARR= 7.2%, P=0.03)

Dr Wilt’s conclusion based on the latest study data was that:

“In men with localized prostate cancer detected during the early PSA era, radical prostatectomy compared to observation did not significantly reduce all-cause and prostate cancer mortality. Absolute differences through at least 12 years were less than 3%”

These results are important findings that should impact the treatment of men diagnosed with early stage, low risk prostate cancer.

The fact that the survival curves do not diverge except for high-risk patients presenting with a PSA > 10ng/mL, may also have an impact on the ongoing PSA prostate screening debate.

If the PIVOT data results in more men being put on watchful waiting/active monitoring, then it should lower the overtreatment that screening currently produces. Urologists will, however, need to be prepared to counsel their patients accordingly and forego the economic benefits that undertaking surgery affords many of them.

Urologists at the EAU in Paris greeted the PIVOT trial data in silence and an absence of social media interaction (I did not see any urologists tweet enthusiastically about it).

Many urologists who have trained many years to perform complex surgical techniques may find the idea of watchful waiting an anathema.

Adopting a policy of watchful waiting in many prostate cancer patients may also place economic pressures placed on those urologists who need a throughput of patients to recover or amortize the cost of expensive technology such as the da Vinci robotic system.

The PIVOT trial data is, however, level 1 evidence based medicine that cannot be ignored.

Hopefully, this analysis of the PIVOT trial data will be published in a peer-reviewed journal in the not too distant future so that it can reach a wider audience than those urologists who attended the AUA 2011 and EAU 2012 plenary sessions.

Update July 18, 2012

The results of the PIVOT trial presented at AUA 2011 and EAU 2012 have been published in the New England Journal of Medicine (online first, July 18, 2012).

Why don’t we have evidence based medicine for robot-assisted radical prostatectomy?

That was the question that I asked Walter Artibani, Professor and Chair of Urology at the University of Verona during the recent European Association of Urology (EAU) annual Congress in Paris.

Urologists have failed as scientists to generate evidence based medicine

Professor Artibani told the assembled media that urologists had failed as scientists in not generating robust clinical data to support the use of the da Vinci robotic system for the removal of the prostate gland (prostatectomy).

Something that I was not aware of until I attended the media briefing was that so called “robotic surgery” is not an automated robot performing the surgery on its own, but instead it’s actually robot assisted surgery.

The da Vinci surgical device (currently the only one on the market) is a telemanipulation system where the surgeon sits at a remote console and operates a surgical cart with three or four arms that are docked with endoscopic instruments that are inserted into the patient.

Professor Artibani in response to my question said:

“After 10 years, the urologic community missed the window to have prospective randomized clinical trial in order to have clear answers.”

What’s more he went on to say that he believed it would be unlikely we could now do a prospective trial that compared robot-assisted prostatectomy to laparascopic prostatectomy to open prostatectomy. The reason for this was that :

“Most of the patients are convinced that the new way, the novel way is the better way.”

The following is a video excerpt of Professor Artibani’s answer to my questions. For digital accuracy, viewers should note that I added in some slides he presented earlier, and included a graphic of the paper he referenced.

http://youtu.be/jXImeY-f9j0

Have the media sensationalized robotic surgery?

Artibani went on to say in his answer to my question that the media and journalists have not always reported the lack of robust data surrounding new surgical techniques:

“It is easy just to give the information that what is new is better and this must be demonstrated by robust data before giving the information. Unfortunately sensationalism is more important than to say and to write robust data.”

Healthcare journalists have an obligation to report on the limitations of new techniques and lack of evidence based medicine is an important one! Gary Schwitzer’s healthcare journalist watchdog, Health News Review, attempts to hold the media to account.

We should clearly challenge surgical practice for which there is a lack of robust clinical data or evidence based medicine, and avoid sensationalism.

However, whatever the limitations of the media reporting, the reason for the lack of evidence based medicine rests firmly with the academic urology community.

Low quality of evidence for Robot-Assisted Laparoscopic Prostatectomy

In an editorial in the journal “European Urology,” Markus Graefen noted the low quality of urology research that was being published did not just apply to robot-assisted prostatectomy. He noted that in urology,

“The number of low-quality papers is increasing; however, the body of evidence and the knowledge we have about the reported outcomes, unfortunately, is not.”

He went on to describe the need to counsel patients on the different surgical approaches available to them:

A patient with a newly diagnosed prostate cancer who is counselled for his therapeutic options today should be informed that several equal surgical approaches are available and that despite all the perfectly styled Web pages, it is not the robot that makes the difference.

He should be informed that there are indeed concerns about oncologic and functional outcomes and also evidence that in some significant papers the traditional surgical approaches look superior.

This editorial suggests that patients should ignore the marketing hype about new equipment or the notion that “new is better,” but instead focus on the experience of the surgeon with that equipment and the functional outcomes that a surgeon obtains in his/her patients.

Patients are interested in functional outcomes and low complication rates

What I heard at EAU from urologists is that patients are interested in a good functional outcome and low complication rate.

There is, however, no level 1 evidence that post-operative urinary incontinence and erectile dysfunction rates are generally better with robot-assisted radical prostatectomy.

Diana Kang and colleagues in a review of seventy-five research publications between 2005 and 2008 that reported robot-assisted laparscopic prostatectomy (RALP) data, concluded that there was a need to raise the standards of urology clinical research:

Our findings draw into question to what extent valid conclusions about the relative superiority or equivalence of RALP to other surgical approaches can be drawn and whether published outcomes can be generalised to the broader community.

There is an urgent need to raise the methodologic standards for clinical research on new urologic procedures and devices.

Men with prostate cancer who are considering surgery should be informed that there is no high-level or robust evidence to show the general superiority of robotic-assisted prostatectomy compared to other surgical techniques for radical prostatectomy.

Hopefully, the demand for evidence based urology treatment will grow, and that lessons have been learned from the way robotic-assisted surgery was introduced. Men with prostate cancer do deserve better.

Kang, D., Hardee, M., Fesperman, S., Stoffs, T., & Dahm, P. (2010). Low Quality of Evidence for Robot-Assisted Laparoscopic Prostatectomy: Results of a Systematic Review of the Published Literature European Urology, 57 (6), 930-937 DOI: 10.1016/j.eururo.2010.01.034

Graefen, M. (2010). Low Quality of Evidence for Robot-Assisted Laparoscopic Prostatectomy: A Problem Not Only in the Robotic Literature European Urology, 57 (6), 938-940 DOI: 10.1016/j.eururo.2010.02.004

Update on Orteronel TAK-700 from EAU 2012 Paris #EAU12

There are no major presentations of phase III clinical trial data at the European Association of Urology (EAU) Congress in Paris this weekend, but interesting clinical and scientific data is still being presented.

If you want to understand the competitive dynamics of the prostate cancer market and the market opportunity with urologists, then you need to be at meetings such as EAU in Europe and AUA in the United States.

There was a lot of interest in yesterday’s advanced prostate cancer poster session at EAU 2012.

I mentioned in a previous post that the radium-223/Alpharadin poster showed the data on skeletal-related events presented last month at ASCO GU in San Francisco.

Another poster that caught my attention for a variety of reasons was the one on orteronel (TAK-700), something that we have not heard too much about.

Activity and Safety of the Investigational Agent Orteronel in Men With Nonmetastatic Castration-resistant Prostate Cancer and Rising Prostate-specific Antigen: Results of a Phase 2 Study

Orteronel (TAK-700) is a selective, non-steroidal inhibitor of 17, 20 lyase, a key enzyme involved in the production of androgens such as testosterone. This is a similar mode of action to abiraterone acetate (Zytiga) that was approved last year in the US & Europe.

Orteronel is being developed by Millennium. Two phase III castration-resistant prostate cancer trials are currently enrolling. The post-chemotherapy trial (NCT01193257) is scheduled to have a primary completion date of September 2013 and the chemotherapy-naïve trial has a primary completion date of January 2013 (NCT01193244) according to clinicaltrials.gov at the time of writing.

It is worth noting that both phase III trials are using the drug in combination with prednisone. I doubt very much that the chemotherapy-naïve trial will show overall survival results by January 2013 (a date earlier than the post-chemo trial). This date must reflect when data on the primary outcome measure of radiographic progression free survival (rPFS) will be obtained.

Does rPFS correlate with overall survival? Many oncology new products have shown progression free survival, but no overall survival.

Is there a market for a “me too” of abiraterone? By the time orteronel comes to market, MDV3100 and Alpharadin will both most likely be approved, plus we will have greater insight into combinations and sequencing by then.

In talking to urologists, there is a clear preference for drugs such as MDV3100, which do not require the administration of concomitant steroids.

The phase II data in the poster presented at EAU yesterday concluded:

In patients with nmCRPC and rising PSA, single agent oral orteronel, at a dose of 300 mg BID without prednisone, was feasible and had manageable toxicities.

While it may be possible to administer orteronel without steroids, given the mechanism of action would it still be as effective? The authors also noted in the poster that 2 patients (out of 38) discontinued treatment due to adrenal insufficiency, suggesting that giving the drug without steroids is going to require active surveillance.

Finally, in thinking about TAK-700, I’m left with the question of whether phase III placebo controlled clinical trials are still ethical in advanced prostate cancer patients? In the post-docetaxel indication, we now have cabazitaxel and abiraterone approved, both of which offer an overall survival benefit. MDV3100 and Alpharadin are also expected to be approved by the FDA later this year.

If we have four new agents available after docetaxel that offer a survival advantage, is it ethical for men with advanced prostate cancer to be offered a placebo? If not, then this means that new products will have to go head-to-head with one of the approved drugs, or offer some additive effect if used in combination.

It will be interesting to see if this important issue is taken up by any of the patient advocacy groups and whether physicians start to raise concerns. Recruitment into placebo controlled trials could end up slower as a result.

Orteronel to me is too similar to abiraterone, which I think will face serious challenge from MDV3100. What the market opportunity for Millennium will be as a result of being late to market is an open question.

Alpharadin Expanded Access Program is Recruiting #EAU12

radium-223-Alpharadin-Expanded-Access-Program-Clinical-Trial-Notice

Picture with permission of Bayer

No new data on radium-223 (Alpharadin) was presented at the European Association of Urology 2012 Congress in Paris today.

Dr Chris Parker presented a poster with similar data to his oral presentation on Alpharadin at the recent ASCO GU meeting. The phase III ALSYMPCA trial results were first presented at ECCO/ESMO in Stockholm last year.

However, one of things I did learn at EAU12 was that Bayer have opened an Expanded Access Program for Alpharadin, that allows eligble advanced prostate cancer patients access to this radiopharmaceutical pending regulatory approval.

I was told by a Bayer representative that a license is required but that they are now approving sites so that they can administer Alpharadin in the United States pending regulatory approval.

Further information is available about the trial (NCT01516762), and inclusion/exclusion criteria are available on the clinicaltrials.gov website. This is good news for advanced prostate cancer patients.

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European Association of Urology 2012 #EAU12 Twitter Coverage

Today sees the start of the 27th annual European Association of Urology (EAU) Congress at the Palais des Congrès in Paris.

The meeting runs from 24-28 February, 2012. Over 10,000 delegates are expected, and more than 1193 abstracts have been accepted for poster and video sessions.

In addition to a scientific programme, this meeting also has a strong educational component with numerous courses through the European School of Urology (ESU) and hands-on-training to improve surgical skills in cooperation with the EAU Section of Uro-Technology (ESUT), the EAU Section of Urolithiasis (EULIS) and the EAU Section of Robotic Urology (ERUS).

If you can’t be in Paris, then EAU have some live webcasts and they will be sharing a lot of the content from the meeting as well as undertaking video interviews. Check out the EAU 2012 Paris Congress website for more information.

For those that are interested in following the twitter coverage of the meeting, the hashtag is #EAU12, and EAU is @uroweb on twitter. You can also use the twitter aggregator below:

Preview of ASCO GU 2012 Prostate Cancer Data

After the recent JP Morgan Healthcare conference, San Francisco remains the destination of choice for forthcoming medical meetings.

Yesterday, saw the start of the 2012 ASCO Gastrointestinal Cancers Symposium (ASCO GI) at Moscone West from Jan 19-21.

In a few weeks time, the 2012 ASCO Genitourinary Cancers Symposium (ASCO GU) will be held at the San Franciso Marriott Marquis from Feb 2-4.

If you are based in San Francisco, you are at the heart of the action. It’s less optimal if you are East Coast based, unless you need the frequent flyer miles and have a good travel budget!

According to the ASCO GU preliminary program there are eight oral abstracts on prostate cancer that will be presented at the meeting on Thursday, February 2. Here’s my preview of a few that caught my attention:

ASCO GU Abstract #1:

MDV3100 Phase 3 AFFIRM trial results

The first presentation of the MDV3100 AFFIRM phase 3 trial results are a late-breaking abstract and my prediction for the highlight of the prostate cancer session at ASCO GU.

So far, all that is known from the November 3, 2011 press release from Medivation/Astellas is that MDV3100 produced a 4.8 month advantage in median overall survival compared to placebo in men with advanced prostate cancer.

This met the primary endpoint of the phase 3 AFFIRM trial, and the study was stopped early as a result. As the press release notes, MDV3100 provided a 37% reduction in risk of death compared to placebo (hazard ratio = 0.631).

Howard Scher (MSKCC) will present the AFFIRM trial results at ASCO GU, and a closer look at the MDV3100 data is eagerly awaited.

ASCO GU Abstract #6:

Effect of denosumab on prolonging bone-metastasis-free survival (BMFS) in men with nonmetastatic castrate-resistant prostate cancer (CRPC) presenting with aggressive PSA kinetics.

Amgen are seeking a new indication for denosumab (Xgeva) in prostate cancer on the grounds that it prolongs bone metastasis-free survival in men with non-metastatic CRPC. The supplemental Biologics Application (sBLA) for denosumab will be discussed at the Oncologic Drugs Advisory Committee (ODAC) meeting on February 8, 2012.

The results from the phase 3, 147 trial were published in The Lancet last November and showed that use of denosumab delayed time to first bone metastasis by 3.7 months and improved bone-metastasis free survival.

Sally Church on Pharma Strategy Blog wrote about the denosumab 147 data presented at the annual meeting of the American Urological Association (AUA 2011) last year.

However, the challenge that Amgen faces is that they have yet to show that use of denosumab in men with prostate cancer results in an improvement in overall survival. While it may delay the spread of prostate cancer to the bone, the gold standard for all the prostate cancer drugs approved to date has been overall survival.

The 147 trial showed that overall survival was similar between those taking placebo and those receiving denosumab (HR 1.01; 95 percent CI: 0.85, 1.20; p=0.91). Hypernatremia and osteonecrosis of the jaw were also reported with a higher frequency in the denosumab group

It is possible that there may be updated data at ASCO GU, but most likely it will be a review of The Lancet data with some subset analysis.

The FDA Center for Drug Evaluation & Research (CDER) plans to provide a free of charge, live webcast of the February 8, 2012 meeting of the Oncologic Drugs Advisory Committee, so I am looking forward to what the committee makes of Amgen’s filing.

ASCO GU Abstract #7:

Vitamin E & the Risk of Prostate Cancer – updated results of the Selenium and Vitamin E Cancer Prevention Trial (SELECT)

Eric Klein will be presenting updated results from the SELECT trial that were previously reported in the October 12, 2011 issue of the Journal of the American Medical Association (JAMA).

The data showed a 17% increase in prostate cancer risk with Vitamin E supplements. Although the program abstract advertises updated data, I’m not expecting the data to differ dramatically from last year’s JAMA paper.

ASCO GU Abstract #8:

Overall survival benefit and safety profile of radium-223 chloride (Alpharadin), a first-in-class alpha-pharmaceutical: Results from a phase III randomized trial (ALSYMPCA) in patients with castration-resistant prostate cancer (CRPC) with bone metastases.

The ALSYMPCA trial data is being presented for the benefit of attendees who did not hear Oliver Sartor’s presentation on radium-223 (Alpharadin) at the NY Chemotherapy Foundation or hear Chris Parker present the trial data at ECCO/ESMO in Stockholm. This makes strong commercial sense, especially as it’s a product that physicians in the United States may know little about.

I blogged extensively about the ALSYMPCA trial results presented last year, and had the privilege to do an interview with Chris Parker from the Royal Marsden Hospital at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO/ESTRO) in Stockholm.

I am not expecting new data to be presented at ASCO GU on radium-223, but it will be interesting to see how the audience views a bone targeted radio-pharmaceutical that unlike denosumab, does provide an overall survival benefit.

The ALSYMPCA trial showed a significant delay in time to first skeletal-related event (SRE) of 13.6 months vs 8.4 months:

AND a median overall survival of 14 months compared to 11.2 months for placebo group:

Alpharadin is on the fast track to FDA approval this year.

My conclusion: If you plan to be at ASCO GU 2012, the prostate cancer data to watch is the first presentation of the MDV3100 AFFIRM trial results.

Robotic Assisted Prostate Surgery does not lead to fewer complications

A survey of patients who had their prostate removed showed there was no significant difference in complication rates between open retropubic radical prostatectomy (ORRP) and robotic assisted laparoscopic surgery (RALRP).

This is an important finding because 85% of prostatectomies in the United States are undertaken using robotic-assisted techniques, yet there has been little published data to show that this technique improves functional outcomes.

At the European Association of Urology (EAU) annual congress last year in Vienna some of the challenges and opportunies with robotic surgery were raised:

lack of data on improved functional outcome
need for licensing of robotic surgeons
high learning curve – it takes 250 patients to become proficient

In reality, we see hospitals marketing their robotic surgery to patients in shopping malls and with advertisements on the side of buses. You can read Gary Schwitzer’s thoughts on some of the recent marketing claims & “gizmo idolatry.”

This is why a survey comparing the results of open to robotic assisted prostate removal surgery is important evidence based medicine. Published online first in the Journal of Clinical Oncology, Barry and colleagues randomly surveyed 800 men who filed Medicare claims between August and December 2008. 685 completed surveys were returned, and information on adverse events was obtained.

The data highlights the dramatic effect on quality of life that prostate cancer surgery can have, irrespective of the surgical technique. The men rated themselves:

31.1% – moderate or big problem with continence (95% CI 27.5 to 34.8%)

88.0% – moderate or big problem with sexual function (95% CI 85.4% to 90.6%)

Breaking this down by technique (robotic surgery versus open prostatectomy):

Continence: 27.1% of men (Open) versus 33.3% (Robotic) – not significant (P=0.113)

Sexual Function: 89.0% of men (Open) versus 87.5% (Robotic) – not significant (P=0.57)

The authors conclude in their JCO paper:

Our results do not demonstrate a lower risk of problems with incontinence or sexual function after RALRP compared with ORRP.

In fact, after adjusting for potential confounders, there was at least a strong trend toward a higher risk of patient-reported moderate or big problems with incontinence following RALRP.

The authors in their discussion do raise the interesting question as to whether patients were led to believe that they would have fewer side effects with robotic surgery, which may have impacted the survey findings. This merits further investigation.

There is clearly a need for patients to give informed consent, and be aware of the risks and complications of prostate cancer surgery, particularly with regards fundamental quality of life issues such as continence or sexual function.

The accompanying JCO editorial by Matthew Cooperberg and colleagues from UCSF is well worth reading and raises the question as to whether men with prostate cancer should expect better outcomes than those reported in the survey?

What the survey by Barry et al did not do is look at the volume of procedures and experience level of the surgeon, both of which are associated with outcomes.

Cooperberg noted that “surgeons performing fewer than 5 prostatectomies per year account for approximately half the national volume.”

A chilling statistic, and if you factor in the learning curve of more than 200 procedures to be competent at robotic surgery, it is perhaps not surprising that some men experience higher complication rates than others.

Which brings me back to the importance of the PIVOT (Prostate Cancer Intervention versus Observation Trial) data presented in the plenary session at the 2011 annual meeting of the American Urological Association (AUA) in May last year.

Why has this practice changing data not been published in a peer-reviewed journal yet?

The fact that the updated PIVOT study results presented at AUA 2011 have not been published (to the best of my knowledge) is a disservice not only to the medical and scientific community, but to men with prostate cancer whose treatment should be guided by evidence-based medicine.

The long-term results of the PIVOT trial presented by Professor Wilt showed no benefit of radical prostatectomy over watchful waiting, except for high-risk patients. Yet, the reality is that many men end up having surgery. This may be considered overtreatment and an exposure of more men than is necessary to the complications of prostatectomy, irrespective of whether this is robotic or open surgery.

The decision to undergo radical prostatectomy should be an informed one, not only as to the risks and benefits of the surgical technique, but also whether the surgery should be performed in the first place as compared to “watchful waiting.”

I hope the paper and editorial published in the JCO this month will generate some debate. Next month I will be at the European Urology Association annual congress in Paris.

References

Barry, M., Gallagher, P., Skinner, J., & Fowler, F. (2012). Adverse Effects of Robotic-Assisted Laparoscopic Versus Open Retropubic Radical Prostatectomy Among a Nationwide Random Sample of Medicare-Age Men Journal of Clinical Oncology DOI: 10.1200/JCO.2011.36.8621

Cooperberg, M., Odisho, A., & Carroll, P. (2012). Outcomes for Radical Prostatectomy: Is It the Singer, the Song, or Both? Journal of Clinical Oncology DOI: 10.1200/JCO.2011.38.9593

Update August 12, 2012 – Paper published in European Urology shows lower incontinence and greater rate of erection recovery with robot-assisted radical prostatectomy

A paper published online (July 20, 2012) in the journal, European Urology by Franceso Porpiglia provides some evidence that robot-assisted radical prostatectomy offers functional benefits to patients. I have not read the full paper only the freely available abstract.

The clinical trial evaluated the functional outcomes of 120 men in a randomized clinical trial where half (n=60) received radical prostatectomy (RARP) that was robot-assisted and the other half (n=60) who had the operation laparoscopically without robot assistance (LRP).

Following the surgery performed by Dr Porpiglia, the functional outcomes between the two groups were compared. Those men operated on with robot assistance showed:

Lower incontinence. “Continence after 3 mo was 80% in the RARP group and 61.6% in the LRP group (p = 0.044), and after 1 yr, the continence rate was 95.0% and 83.3%, respectively (p = 0.042)”
Better erection recovery. “Among preoperative potent patients treated with nerve-sparing techniques, the rate of erection recovery was 80.0% and 54.2%, respectively (p = 0.020).”

The challenge of this study is that although it was randomized, it reflects the results of only one surgeon with a small number of patients.

Dr Matthew Cooperberg (@cooperberg_ucsf) was quoted by Reuters saying that this was likely the best study we were going to get showing the benefits of RARP over LRP. On twitter he said the real question was now between radical prostatectomy and external radiation therapy (XRT).

https://twitter.com/cooperberg_ucsf/status/233427660708126721

Prostate Cancer Session at AACR-NCI-EORTC Molecular Targets San Francisco

By Pieter Droppert on November 17, 2011

The recent AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics international conference in San Francisco was an informative meeting.

What I particularly liked was the strategic overview that took place in many of the plenary sessions.

As an example, Johann de Bono, Professor of Experimental Cancer Medicine at The Institute of Cancer Research/The Royal Marsden in London highlighted the potential drug development targets based on prostate cancer biology:

Androgen Receptor (AR)
Heat Shock Proteins (Hsp)
Signaling: HER3, MET, IGF-1R, CCL2, IL-6, Src
PI3K/AKT/TOR signaling
PARP and BRCAness
Estrogen receptor (ER)
c-MYC & CHK1

His presentation discussed the possible therapeutic approaches, and complexity involved in developing novel targeted therapies for prostate cancer.

This is something that I expect we will hear more of at the AACR special conference on Advances in Prostate Cancer Research early next year.

In particular, de Bono discussed drug development strategies to target androgen receptor signaling, and some of the future challenges including:

Proving to the regulatory authorities that circulating tumor cell (CTC) count falls are a robust immediate endpoint of overall survival
Developing improved imaging for bone metastases

As a side note, there were several posters for cabozantinib (XL184) at the meeting (available on the Exelixis website), including preliminary research on computer-aided quantitative bone scan assessment.

However, as de Bono mentioned in his presentation, “diffusion weighted MRI shows hot spots not detected by bone scans.”

2010 and 2011 were good years for prostate cancer drugs, and with new approvals for MDV3100 and radium-223 (Alpharadin) expected, 2012 is set to be another “grand cru” year, to paraphase Bertrand Tombal.

If you were not able to make it to San Francisco for the Molecular Targets and Cancer Therapeutics conference, webcasts of many sessions will be available on the AACR site.

Chemotherapy Foundation Symposium Prostate Cancer Update

This morning the 8am session at the Chemotherapy Foundation Symposium (The Greenspan Meeting) in NYC featured a review of current developments in Prostate Cancer.

The informative 1.5 hour session covered a lot of ground with the presenters reviewing clinical data for:

Radium-223 Chloride: a new option for CRPC (Oliver Sartor)
Pomegranite extract for Rising PSA (Michael Carducci)
XL184 in mCRPC (David Smith)
Optimizing patient selection for sipuleucel-T (Simon Hall)
Intermittent androgen suppression for prostate cancer (Laurence Klotz)
Lenolidomide/docetaxel in CRPC (Daniel Petrylak)

The highlight, in my opinion, was Oliver Sartor’s excellent presentation on radium-223 chloride (Alpharadin) in which he cogently outlined its mechanism of action. He explained that radium-223:

targets osteoblastic bone metastases by acting as a calcium mimic
is a bone-seeking calcium mimetic that binds to hydroxyapatite
has preferential uptake in areas of new bone formation

As mentioned previously on this blog, there are critical differences between an alpha emitter such as radium-223 and other bone-seeking radiopharmaceuticals that are beta emitters.

Sartor presented some excellent slides that showed how alpha emitters require much fewer DNA hits to kill cells, are short range and have a higher initial energy per particle. In other words they are very effective at short range within the bone microenvironment, something that Chris Parker from The Royal Marsden Hospital mentioned in his interview from ECCO/ESMO in Stockholm.

Sartor concluded his Chemotherapy Foundation Symposium presentation by reflecting on “where do we go from here” in prostate cancer? Some of his observations were:

We are currently in a sequencing paradigm. Drug A then B then C
We need to combine active agents to give the best results, that is our next challenge
How are we going to afford it all?

Sartor succinctly highlighted where the rubber currently hits the road, and left the audience with plenty to reflect upon. I am sure we can expect further debate on sequencing and combination possibilities at medical and scientific meetings in 2012.

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MDV3100 shows survival in Advanced Prostate Cancer

Prostate cancer is the second leading cause of cancer death in men, so it was good news this morning when Medivation & Astellas issued a press release that showed positive data from the phase 3 AFFIRM trial for MDV3100.

MDV3100 produced a 4.8-month advantage in median overall survival compared to placebo.

The estimated median survival for men treated with MDV3100 was 18.4 months compared with 13.6 months for men treated with placebo.

MDV3100 provided a 37 percent reduction in risk of death compared to placebo (Hazard Ratio=0.631).

To put the 4.8 month survival advantage in context, this compares favorably with 3.9 months for abiraterone (Hazard Ratio =0.646), in the COU-AA-301 trial.

Positive data was expected given the sound scientific rationale behind MDV3100 and the preliminary data (abstract 4501) presented at the ASCO annual meeting this year. J Clin Oncol 29: 2011 (suppl; abstr 4501).

The drug has a high affinity for the androgen receptor (AR) that is highly expressed on prostate cancer cells. You can read an excellent interview on Pharma Strategy Blog with Charles Sawyers, who was one of the co-inventors.

MDV3011 blocks the androgen receptor (AR) from moving into the nucleus and activating growth genes and is a more complete inhibitor of AR than bicalutamide.

One hot topic of conversation at ASCO was the potential to combine MDV3100 (androgen receptor blocker) with abiraterone acetate (Zytiga) (androgen synthesis inhibitor), thereby shutting down upstream and downstream activity of the driving receptor in advanced prostate cancer. The scientific rationale for this appears sound, so it is likely that a combination clinical trial may well be done to test this hypothesis at some point in the future.

MDV3100 has a significant advantage over abiraterone acetate (Zytiga) in that concomitant steroids are not required. Daily steroids have their side effects. Urologists in particular will be attracted to MDV3100 and its ease of use.

Clinical trials in prostate cancer are ongoing with a multitude of new emerging therapies including TAK-700, Cabozantinib (XL184), radium-223 chloride (Alpharadin), BPX-101, Prostvac-VF, ipilumumab, Custirsen (OGX-011), dasatinib (Sprycel), lenalidomide (Revlimid) and ARN-509 to name but a few.

It is a therapeutic area with a lot going on after very little activity for a decade. The positive interim data for MDV3100 announced today is good news for prostate cancer patients, and we await presentation of the data next year.

Medivation and Astellas plan to hold a pre-NDA meeting with the U.S. Food and Drug Administration (FDA) in early 2012, so US approval could be possible later next year.

Biotech Strategy Blog

Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Cancer Immunotherapy

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