EAU 2012 Congress | Biotech Strategy Blog

The Mannogram – how imaging may revolutionize prostate cancer diagnosis

“The Mannogram – Yes we scan” Jelle Barentsz, Professor of Radiology at Radbound University, Nijmegen, The Netherlands told the assembled media at the recent European Association of Urology (EAU) annual Congress in Paris.

Professor Barentsz described how advances in magnetic resonance imaging (MRI), and in particular multi-parametric MRI (Mp-MRI) offer the potential for the improved detection and characterization of prostate cancer.

In the same way there is a mammogram that women use for breast cancer screening, Professor Barentsz raised the possibility that using magnetic resonance imaging, men could have a mannogram to screen and diagnose prostate cancer.

Some of the advantages of multi parametric MRI he highlighted include:

Prediction of tumor aggression
Prediction of low vs intermediate or high grade prostate cancer correctly in 95% of men in a trial as compared to 54% with TRUS (trans-rectal ultrasound guided) biopsy
In cases where there was a negative TRUS biopsy initially, mp-MRI and MR guided biopsy detected prostate cancer in 41% (108/265 of trial participants), with 87% of the prostate cancer detected being significant.

It is beyond the scope of this post to go into the physics of multi-parametric MRI or discuss in more detail the imaging trial data on which the above conclusions are based. However, for those interested in this area, I have included details of some of the references Professor Barentsz kindly provided at the end of the post.

Why do we need new techniques for prostate cancer diagnosis?

During their lifetime 1 in 6 men will be clinically diagnosed with prostate cancer. There are 899,000 new cases and 258,000 deaths per year in Europe.

The current diagnostic tools of digital rectal examination (DRE), serum prostate specific antigen (PSA) and trans-rectal ultrasound guided (TRUS) biopsy have a number of limitations for prostate cancer detection.

This includes a lack of specificity (PSA = 36%), insensitivity (DRE = 37%) or failure to detect cancer due to sampling error with TRUS biopsy (more than 20% of cancers are not detected on first biopsy).

The result is that we end up with large numbers of men with elevated men or rising PSA, who have repeat biopsies. This comes at a high cost to health care providers, the uncertainty of diagnosis and the discomfort that comes with a TRUS biopsy (TRUS-Bx).

Many men undergo diagnostic procedures only to find they don’t have prostate cancer. One of the key issues in the prostate cancer screening debate is this unacceptable harm/benefit ratio.

Prostate biopsy to confirm cancer diagnosis is an invasive procedure as Professor Jenny Donovan, Head of the School of Social and Community Medicine, at the University of Bristol told the EAU Congress.

In a plenary session, Prof Donovan described some of the initial findings from the PROBE (Prostate Biopsy Effects study), which looked at 1,147 men who received a TRUS-Bx.

“The majority of men tolerated biopsy reasonably well – over 60% experience minor symptoms. However, around one third experience symptoms that bothered them,” she said.

Professor Donovan went on to give examples of some of the feedback on the biopsy experience that researchers obtained:

“I found it incredibly painful and distressing – biopsy with a nail gun,” one man in the PROBE study said.

Data presented by Professor Donovan showed that after the procedure, 11% of men would not want another biopsy (this rose to 20%) seven days later.

Magnetic Resonance Imaging Guided Biopsy may offer benefits

Given the discomfort that many men experience with TRUS biopsy, and the fact a negative biopsy does not automatically mean no cancer (there’s a risk of sampling error), the use of MR guided biopsy may offer significant benefits.

One is that instead of 12 cores being sampled by the TRUS-Bx, only 2 cores are obtained using the MR guided biopsy technique that Professor Barentsz described.

Personally, I would prefer to have two precise cores samples taken from me through imaged based guidance, than have a TRUS biopsy that is like a nail gun that shoots in 12 sampling rods into the target area of the prostate. This would be like the difference between a sniper rifle and a blunderbuss, metaphorically.

One of the practice implications of this is that radiologists may end up performing MR guided biopsies instead of urologists performing TRUS biopsies.

Urologists in private practice or those who are paid per procedure may not be happy about the practice changing implications that may result.

The MR imaging research that Professor Barentsz described at EAU is not without its limitations and one concern is the reproducibility of advanced imaging techniques outside of an expert university or academic setting. I put this question to Professor Barentsz in the media briefing and have included an excerpt of his reply that you can listen to:

According to Professor Barentsz, the imaging techniques for MR guided prostate biopsy are readily reproducible outside the academic environment with guidelines already in place for standardized acquisition protocols and structured interpretation of results.

“We are now at the point that the standardization of prostate MRI as well as the standardization of reporting with all kind of computer assistance is a fact and not fiction anymore,” said Barentsz.

The European Society of Urogenital Radiology (ESUR) recently published MR guidelines, that include a structured reporting system, called PI-RADS (prostate imaging, reporting, and data system). This has been adopted in the United States by the American College of Radiology (ACR).

Before men with prostate cancer can expect to see these advanced imaging techniques used outside of expert centers, however, urologists and radiologists will need to agree on the benefits they offer and adapt their practice accordingly. Urologists may be reluctant to move away from TRUS biopsy, so it is likely widespread implementation will take some time and require education, and explanation of the evidence based medicine that supports the proposed change in practice.

The conclusion from Professor Barentsz’s EAU presentation is that imaging looks likely to play an increasing role in the diagnosis of prostate cancer.

It will be an exciting area to watch. The idea of a Mannogram has the potential to become a reality that would benefit the 1 in 6 men who will be diagnosed with Prostate Cancer during their lifetime.

References

Hambrock, T., Somford, D., Huisman, H., van Oort, I., Witjes, J., Hulsbergen-van de Kaa, C., Scheenen, T., & Barentsz, J. (2011). Relationship between Apparent Diffusion Coefficients at 3.0-T MR Imaging and Gleason Grade in Peripheral Zone Prostate Cancer Radiology, 259 (2), 453-461 DOI: 10.1148/radiol.11091409

Hoeks, C., Schouten, M., Bomers, J., Hoogendoorn, S., Hulsbergen-van de Kaa, C., Hambrock, T., Vergunst, H., Sedelaar, J., Fütterer, J., & Barentsz, J. (2012). Three-Tesla Magnetic Resonance–Guided Prostate Biopsy in Men With Increased Prostate-Specific Antigen and Repeated, Negative, Random, Systematic, Transrectal Ultrasound Biopsies: Detection of Clinically Significant Prostate Cancers European Urology DOI: 10.1016/j.eururo.2012.01.047

Barentsz, J., Dickinson, L., & Sciarra, A. (2011). Re: Axel Heidenreich. Consensus Criteria for the Use of Magnetic Resonance Imaging in the Diagnosis and Staging of Prostate Cancer: Not Ready for Routine Use. Eur Urol 2011;59:495–7 European Urology, 60 (1) DOI: 10.1016/j.eururo.2011.03.013

Hambrock, T., Hoeks, C., Hulsbergen-van de Kaa, C., Scheenen, T., Fütterer, J., Bouwense, S., van Oort, I., Schröder, F., Huisman, H., & Barentsz, J. (2012). Prospective Assessment of Prostate Cancer Aggressiveness Using 3-T Diffusion-Weighted Magnetic Resonance Imaging–Guided Biopsies Versus a Systematic 10-Core Transrectal Ultrasound Prostate Biopsy Cohort European Urology, 61 (1), 177-184 DOI: 10.1016/j.eururo.2011.08.042

Barentsz, J., Richenberg, J., Clements, R., Choyke, P., Verma, S., Villeirs, G., Rouviere, O., Logager, V., & Fütterer, J. (2012). ESUR prostate MR guidelines 2012 European Radiology, 22 (4), 746-757 DOI: 10.1007/s00330-011-2377-y

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).

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.

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