Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts from the ‘Prostate Cancer’ category

Excellent news in Advanced Prostate Cancer – Medivation's MDV3100 meets primary endpoint

By on November 3, 2011

It’s not often that you wake up to really exciting news in the cancer field, but that’s what happened this morning with Medivation’s announcement on the interim analysis of their androgen receptor (AR) antagonist, MDV3100:

“As reported by the IDMC, 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).

The IDMC further determined, considering the observed safety profile, that MDV3100 demonstrated a favorable risk-to-benefit ratio sufficient to stop the study.”

The 4.8 month improvement in OS in post-chemo setting is superior to that previously reported for abiraterone (Zytiga), which had a 3.9 month advantage over placebo and received regulatory approval in the US and EU earlier this year.

This is great news for patients, for Medivation and also for Charles Sawyers at MSKCC who originally invented the MDV3100 compound. If you are interested in the MDV3100 story, you can read my interview with Dr Sawyers posted earlier this year.

There are several points to note about these results:

  • MDV3100 does not require concomittant steroid therapy as abiraterone does, this is huge for urologists who as surgeons do not generally want to manage side effects.
  • Given the excellent results in the post chemotherapy setting, I would expect the survival advantage in the pre-chemotherapy session for both therapies to be more than 6 months.
  • Ultimately, as hormone therapy, I can see the real advantage for MDV3100 being as a more potent and complete inhibitor of the AR than bicalutamide, so there is a huge potential for MDV3100 as ADT therapy in the earlier stages of disease.

With regards to filing, Medivation announced that:

“Medivation and Astellas plan to hold a pre-NDA meeting with the U.S. Food and Drug Administration (FDA) in early 2012 and will provide an update on regulatory timelines for MDV3100 subsequent to that meeting.”

At this rate, I would expect to see MDV3100 approved sometime in 2012.

The future is looking very bright indeed for patients with advanced prostate cancer – these new therapies offer the potential with sequencing to extend lives significantly.

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A year in the life of Pharma Strategy Blog

By on October 31, 2011

Last week brought the first anniversary of this blog since moving to WordPress as a platform, but as luck would have it, I was snowed under with more work than usual.

Several people have asked about the stats here recently, so it seems a good time as any to do an annual review. Although this blog has been up and running since 2006, it only started on WP on October 24th 2010.

In the last twelve months, PSB has seen the following activity:

  • 614K reads, with around 50-60K reads per month
  • 337K visitors, approx. 30K visitors per month

The busiest day was 6th June, with nearly 5K reads, thanks to a kind link from Matt Herper of Forbes Health.  Ironically, the interim and eagerly anticipated MDV3100 phase III data from Medivation is now due before the end of the year.  More on that when the announcement comes out!

What were the most popular posts? Here’s the Top Ten on Pharma Strategy Blog from the last year based on hits:

  1. PI3K: a hot topic in cancer research
  2. Update on PARP inhibitors
  3. PLX4032 phase III data in metastatic melanoma
  4. Improved survival with ipilimumab in metastatic melanoma
  5. Crizotinib and ALK rearrangements: Ross Camidge interview
  6. Abiraterone/Zytiga FDA approval
  7. Interview with Charles Sawyers
  8. PLX4032 in metastatic melanoma
  9. Update on PI3K from ASCO
  10. Brentuximab Vedotin (SGN-35) for Relapsed CD30-Positive Lymphomas

In some ways, the popularity of these particular posts are no surprise, since if you asked me to name the hot topics in oncology this year, I would have said:

  • ALK in lung cancer
  • BRAF and CTLA4 in melanoma
  • Abiraterone in advanced prostate cancer
  • ADCs and brentuximab

It wasn’t all positive though, as the ongoing PARP story has been notable largely for the negative data. That may change in the future as scientists and clinicians grapple with finding the right targets and sub populations to aim these therapies at.

I was particularly pleased to see that PI3K resonated with the audience as this one of my favourite pathways, although we still have a long way to go to crack the nut with this target.

A big thank you to everyone who read PSB, posted comments, shared articles or the many email exchanges that have taken place; it is much appreciated and I hope that you have enjoyed reading my thoughts and commentary.

Come December, I will post the annual review and predictions for 2012, but in the meantime, normal blog commentary on cancer related topics will resume tomorrow.

BOLERO2 data in breast cancer impresses at ECCO 2011

By on September 27, 2011

This year I decided to write some longer posts from the ECCO/EMCC meeting owing to the amount of potentially paradigm changing data coming out. These in depth op eds will roll out over the next few days.

Quite a few people have been asking what my picks of the conference are, so here goes, in order of Wow factor (purely from my perspective):

  1. Everolimus BOLERO-2 data in ER/PR+ HER2- breast cancer
  2. Alpharadin in advanced prostate cancer
  3. T-DM1 in HER2+ breast cancer
  4. Vismodegib phase III data in basal cell carcinoma

You can read more about the Alpharadin data on the companion Biotech Strategy Blog, but I will put up a post in the pros and cons of this therapeutic later in the week. It’s going to be very interesting indeed to see how this pans out.

Why did I pick the everolimus (Afinitor) data first over the others?

Well, regular readers here on PSB will know that I’m a great believer in

a) targeted therapies and
b) identifying mechanisms of resistance to determine logical combinations

We know that the PI3K-mTOR pathway is dysregulated in hormonal sensitive breast cancer leading to resistance, so a logical approach would be to treat women whose initial AI therapy has failed with another, but add in an mTOR or PI3K inhibitor. That’s exactly the case here.

The results? Simply stunning!

Jose Baselga presented the BOLERO-2 data to a packed audience. When he showed the slide for PFS, there were gasps in the audience around me – a shift in favour of the treatment arm (everolimus plus exemestane) over control (placebo + exemestane) not of the usual 1-2 months, but 6.5 months:

BOLERO-2 data at ECCO 2011

The side effect profile was consistent with what we know about mTOR and Aromatase inhibitors. One thing I would very much like to see is some subset analysis to see what factors separated the super responders from the average responders. This trial tested the combination in a general unselected population, but it would be nice to see if any factors can be derived from the data that suggests what might be predictive of response.

While these results are a major paradigm shift in women with hormonally sensitive breast cancer, the big question is can we do even better?

We also know from basic science that mTOR upregulates AKT, so eventually adaptive resistance will occur through that route too, but you can see where the next round of logical therapies might emerge in future. The current batch of AKT inhibitor have some challenging side effects when used in combination, but next generation of inhibitors might have a more tolerable and improved side effect profile.

All in all, I thought the BOLERO-2 data were my pick of the conference for major practice changing data and I hope to see this data submitted for approval to the Health Authorities very soon. This development is very good news indeed for women with ER/PR+ breast cancer.

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What’s hot at ECCO, ESMO, EMCC in Stockholm 2011?

By on September 21, 2011

After a wild day yesterday once we realised Continental had mysteriously and unaccountably changed our flights to Stockholm from Weds to Weds to Thurs to Tues, it seems that Cinderella will be going to the ball after all.

European Multidisciplinary Cancer Conference (EMCC) here we come, whew!

There are a couple of sessions I’m particularly looking forward to this year:

    1. Presidential Symposium on Sat 25th with talks from some of the leading lights in translational research:
      • Tak Mak (U Toronto) on metabolism and cancer
      • Jose Baselga (MGH) on the challenges of personalised medicine
      • Gordon Mills (MDACC) on the future of personalised medicine

 

    1. Various abstract highlights include:
      • Update on phase II ERIVANCE data for the Hedgehog inhibitor, vismodegib, in basal cell carcinoma (see phase I data from AACR)
      • Biomarkers, including VEGF-A in the bevacizumab trials and an update on KRAS
      • Phase II T-DM1 (trastuzumab emtansine) data in breast cancer
      • Reversing drug resistance in breast cancer (Mon 27th)
      • Updated data from the phase I and III (BRIM3) studies of vemurafenib (Zelboraf) in BRAF V600E-mutation positive metastatic melanoma (will be interesting to see how this compares to the ASCO data
      • Update on therapies in prostate cancer, including new phase III Alpharadin data (see Biotech Strategy Blog)

 

  1. Scientific symposia on PARP inhibitors and PI3K inhibitors (both on Tues 28th). I’m gutted these two important sessions clash, as they are both key events I’d love to attend 🙁

All in all, it promises to be a fun and interesting meeting. For those interested, here’s the link to the full details of the EMCC programme.

Social media comes to ECCO

 

The official Twitter hashtag of the meeting is #emcc2011, a bit long I know, and I would much rather have the shorter, more descriptive and well known #ECCO or #ESMO, but it is a three organisation event afterall, with ECCO, ESMO and ESTRO all involved. You can also follow the EMCC conference organisers on Twitter (@EuropeanCancer).

This inevitably creates branding issues given it seems everyone in the industry has been seemingly asking me over the last two weeks if I’m going to ECCO or ESMO in equal measures! None outside of Twitter have mentioned EMCC at all. Ah well.

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Custirsen – a new treatment for castrate resistant prostate cancer?

By on August 8, 2011

I’ve been following the development of Oncogenex’s custirsen for a while based on various posters presented at meetings such as ASCO and AUA, but with the publication of phase II data in prostate cancer, it seems a good time to discuss the compound in more detail.

According to Oncogenex:

“OGX-011, also known as custirsen sodium, inhibits the production of clusterin, a protein that is associated with treatment resistance in a number of solid tumors, including prostate, breast, non-small cell lung, ovarian, and bladder cancers.”

Essentially, I think of it a chemo-enhancer, although more technically, it seems to help delay the onset of resistance developing by targeting clusterin (CLU).  CLU is a stress-activated cytoprotective chaperone.  It is upregulated by a several cancer drugs and confers resistance when overexpressed.

Low levels of CLU are therefore more desirable and may be useful as a predictive biomarker of response.

Previous data on custirsen from the phase II front-line trial showed an encouraging shift to the right in the survival curves, validating the hypothesis that resistance is delayed:

The current phase II clinical trial received support from both Sanofi and Oncogenex. Results were reported by Saad et al., (2011), who assessed the weekly administration of custirsen in combination with either docetaxel or mitoxantrone in second-line metastatic castrate resistant prostate cancer (CRPC).  Patients had previously been treated with a minimum of 2 cycles of a docetaxel-based chemotherapy regimen and progressed during or within 6 months of discontinuation of docetaxel treatment.

Overall, patients (n=42) were randomized to receive either docetaxel + prednisone + custirsen (DPC) or mitoxantrone + prednisone + custirsen (MPC).

What did the data show?

Given that the preclinical in vitro and in vivo models have demonstrated the potential of custirsen to enhance chemotherapy and reduce docetaxel resistance, I was keen to see how the concept would pan out in humans.  We all know that preclinical evidence is no guarantee of success in clinical trials!  Although the primary goals of the trial were to measure safety and tolerability, the effects on tumour response and disease progression were interesting.

DPC (n=20):

  • Received: median of eight cycles
  • Overall survival:15.8 months
  • TTPP: 10.0 months
  • 10 of 13 (77%) evaluable patients had pain responses
  • Three of 13 (23%) evaluable patients had objective partial responses
  • PSA declines of ≥90%, ≥50%, and ≥30% occurred in 4 (20%), 8 (40%) and 11 (55%) patients, respectively.

MPC (n=22):

  • Received a median of six cycles
  • Overall survival was 11.5 months
  • TTPP was 5.2 months
  • 6 of 13 (46%) evaluable patients had pain responses
  • No objective responses were observed
  • PSA declines of ≥50% and ≥30% occurred in 6 (27%) and 7 (32%) patients, respectively.

Based on experience, we would expect the results with docetaxel chemotherapy to be better than mitoxantrone, since the latter is only palliative at best.

Additionally, custirsen treatment was shown to significantly decrease levels of the target protein, CLU, and low serum CLU levels during treatment demonstrated superior survival.

Two phase III trials in combination with docetaxel are now ongoing in both the first and second line setting in CRPC.  The trials are currently enrolling patients, so results will not be available for a while, ie 2013 at the earliest.

Many of you will remember the video discussion from the American Urological Association meeting earlier this year, where we highlighted the potential for custirsen in combination with an AR antagonist such as MDV3100 from Medivation/Astellas.  For those interested, the initial data from the custirsen/MDV3100 combination is shown in the short vlog.

In the meantime, the results look most encouraging, although there is a-ways to go yet, since phase II data is no guarantee of phase III performance.

{Update: Luke Timmerman from Xconomy posted about the slow recruitment to the phase III trials and the protocol amendment to include Sanofi’s cabazitaxel (Jevtana).

References:

ResearchBlogging.orgSaad, F., Hotte, S., North, S., Eigl, B., Chi, K., Czaykowski, P., Wood, L., Pollack, M., Berry, S., Lattouf, J., Mukherjee, S., Gleave, M., & Winquist, E. (2011). Randomized Phase 2 Trial of Custirsen (OGX-011) with Docetaxel or Mitoxantrone in Patients with Metastatic Castrate-Resistant Prostate Cancer: CUOG Trial P06c Clinical Cancer Research. DOI: 10.1158/1078-0432.CCR-11-0859

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How picking up prostate cancer earlier may improve outcomes

By on August 4, 2011

Prostate cancer is very much in the news this morning, not all for good reasons though.

Dendreon’s Provenge launch to community oncologists did not go well

Dendreon’s stock is in free fall after the company missed it’s earnings and revenue expectations rather badly yesterday.  Adam Feuerstein of The Street has a nice overview of the 2Q earnings call for those of you interested.

There are a couple of things that come to mind though:

  1. The reimbursement may well have a broader impact on the landscape than many realise – CMS may pay for a drug or vaccine, but it doesn’t always pay for the surrounding expenses associated with it*
  2. The “cost dense” issue is offset by ipilimumab (Yervoy) doing better than expected in their metastatic melanoma launch despite a higher overall price (execution matters!)
  3. The root of Dendreon’s problem may well be lack of demand and healthy scepticism from medical oncologists over the value of Provenge relative to the cost:benefit (no impact on tumour shrinkage, bone pain, etc; patients just live a little longer)
  4. Strategy and execution are key in cancer launches to community oncologists

* There are some excellent reimbursement experts out there such as my good friend Bobbi Buell at Covad who steer companies through this kind of minefield.  In fair disclosure, I know I appreciated and valued her solid advice when I was at Novartis and we launched Gleevec in CML.  Having such expertise is a necessity, not a luxury, these days.

Medivation’s MDV3100 may have new opportunities

There was good news from Medivation that caught my interest.  Medivation are developing their androgen receptor (AR) antagonist, MDV3100, in castrate resistant prostate cancer pre and post chemotherapy, with interim results from the latter possibly expected by the year end.  Today, the company announced some positive preclinical data in breast cancer:

“Researchers at the University of Colorado Denver… provide evidence that MDV3100 inhibits proliferation of breast cancer cells.

In different cell-based assays, MDV3100 was able to inhibit both androgen- and estrogen-mediated breast cancer cell proliferation.”

What are the significance of these findings?  Well, the company quoted one of the study authors, Dr Jennifer Richter:

“Our findings are exciting because they challenge the existing idea that androgens are protective in breast cancer by demonstrating that androgens can stimulate proliferation of breast cancer.

These preclinical data show that MDV3100 suppresses androgen-driven breast cancer cell growth and, surprisingly, also suppresses estrogen-driven breast cancer cell growth.”

I think it would be reasonable to expect a phase I clinical trial to evolve soon to test the hypothesis in women with hormone-sensitive breast cancer.

TMPRSS2:ERG may be a more useful marker than PSA in prostate cancer

The big news that really cheered me most this morning, though, was new  data from Science Translational Medicine showing the feasibility of a simple urine test to pick up signs of prostate cancer potentially earlier than we do now. Having had a father who was suddenly diagnosed with stage IV disease, hearing about a test that may help diagnose it earlier than currently feasible with biopsies or PSA is a most welcome advance.

Back in 2005, Arul Chinnaiyan’s lab reported a fusion between two genes present in around half of all prostate cancers called TMPRSS2:ERG.  When the two genes, TMPRSS2 and ERG, combine, they cause aberrant activity and drive prostate cells to grow out of control, leading to cancer.  This is in much in the same way BCR-ABL drives aberrant activity in chronic myeloid leukemia (CML).  The next step after the discovery was to evaluate the reliability and faithfulness of the gene in indicating whether men had prostate cancer.

In the latest report, the researchers measured the level of the fused gene in the urine of men (n=1312) with high PSA levels in their blood, then looked at TMPRSS2:ERG levels, tumour volume and clinically significant prostate cancer, and PCA levels.  They analysed the data to see if the two markers were a good indication of prostate cancer or not.

Half of the men sampled were found to have the TMPRSS2:ERG gene, confirming previous research by the group.

The results also demonstrated:

 “TMPRSS2:ERG, in combination with urine prostate cancer antigen 3 (PCA3), improved the performance of the multivariate Prostate Cancer Prevention Trial risk calculator in predicting cancer on biopsy.”

Essentially, this means that by combining the TMPRSS2:ERG results with PCA data, the group have found a way to stratify men with prostate cancer in terms of risk – in other words, they have a larger and more invasive tumour that requires aggressive treatment.

The diagnostic technology was developed by Gen-Probe, so I think it would be reasonable to assume the company will submit the data to the FDA for approval once further tests have been completed to evaluate accuracy and specificity of the test.  If those are successful, we may well have a new diagnostic test for prostate cancer in the not too distant future.

It goes without saying that picking up aggressive disease earlier and treating it effectively will likely lead to better outcomes for men with prostate cancer.

 

References:

ResearchBlogging.orgTomlins, S., Aubin, S., Siddiqui, J., Lonigro, R., Sefton-Miller, L., Miick, S., Williamsen, S., Hodge, P., Meinke, J., Blase, A., Penabella, Y., Day, J., Varambally, R., Han, B., Wood, D., Wang, L., Sanda, M., Rubin, M., Rhodes, D., Hollenbeck, B., Sakamoto, K., Silberstein, J., Fradet, Y., Amberson, J., Meyers, S., Palanisamy, N., Rittenhouse, H., Wei, J., Groskopf, J., & Chinnaiyan, A. (2011). Urine TMPRSS2:ERG Fusion Transcript Stratifies Prostate Cancer Risk in Men with Elevated Serum PSA Science Translational Medicine, 3 (94), 94-94 DOI: 10.1126/scitranslmed.3001970

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Pharma and Social Media: Update on abiraterone in advanced prostate cancer

By on August 3, 2011

“Fully 71% of online Americans use video-sharing sites such as YouTube and Vimeo, up from 66% a year earlier. The use of video-sharing sites on any given day also jumped five percentage points, from 23% of online Americans in May 2010 to 28% in May 2011.”

Pew Internet (2011)

This is a trend I’ve also noticed amongst my friends over the past year, largely driven by more of them using smartphones and iPads, which make sharing and watching video a whole lot easier.

In the past, I’ve been rather frustrated with Pharmaland and their resolutely horrid web 1.0 branded and unbranded websites that have tiny text, are heavy on flash or not mobile optimised, making sharing or even reading challenging, especially on mobile gadgets. Watching a useful video online, but not being able to share it on Twitter or Facebook with others, is one of those typical desk bang moments – why not if you can share the link to the website?  The world has moved on in terms of how we interact with websites and people online.

Thus I usually end up clicking out and forgetting about them altogether, unless I really need the Prescribing Information (PI) and have to spend a few minutes scrolling and hunting down a miniscule small link that is almost impossible to click without hitting the adjacent link next to it.

Then every once in while something beautiful comes along…

Yesterday, someone outside the US emailed me asking about access to abiraterone (Zytiga) outside the US, so I went on my iPad and to my delight and surprise found this on the Healthcare Professionals page:

abiraterone / Zytiga

Several key points to note here:

  1. You can share information with others by email and Twitter
  2. The PI was easy to find and click on
  3. The mechanism of action (MOA) video on Vimeo was high quality, interesting and sharable
  4. You can sign up for updates or view press releases easily
  5. The reimbursement support information was also easy to access
  6. The UI is uncluttered, has nice large text and is easy to navigate at a glance

In fact, the whole site was nicely laid out and easy to see things, click where you need to go and navigate with the well-thought out UI.  I didn’t have to pinch the screen once, which made a nice change.

Now, there are some glitches such as the patient information was a bit sparse and clicking the Contact Us section took me to the main Janssen website rather than a contact page, forcing me to scroll around looking for it there (hidden at the bottom in pale grey).  There’s no international number or email address when you finally find it, leaving me wondering what to advise my reader who contacted me for help.  This is where providing global Expanded Access Programs or local country contact details can be helpful – they will inevitably reach out, so not providing any help online is a tad antisocial.  There is more than just USA patients with advanced prostate cancer out there, after all.

If anyone from Janssen or Ortho Biotech Global is reading this and could point me in the right direction for helping patients and caregiver outside the US that would be great, as several enquiries a month come in on this topic.  There’s nothing worse than no information or not being able to help.  Companies ultimately live or die on seamless customer service and helping people with their needs.

The experience was pretty positive and I really liked the abiraterone website – it’s a good example of how nice UI design can make a huge difference to the UX for those visiting.  Whichever digital agency was responsible for this site did a very nice job so far and it breaks the cluttered, awkward to navigate with uncomfortably tiny font product website one normally comes across in this field – well done!

I’m hoping the Patient section will soon have some useful information to rival the HCP portal.  Putting in country contact details will be a good start in the right direction, as will information about ongoing clinical trials and a well designed, easy to read patient brochure about the disease, treatment and reimbursement information.  Yes – they do ask about the price and how they can save money – we get emails on that very topic every month too.

An excellent start overall – looking forward to seeing more developments in the near future!

Managing bone metastases with denosumab in prostate cancer: an interview with Dr Neal Shore

By on May 19, 2011

At the annual American Urological Association (AUA) meeting this week in Washington DC, Dr Matthew Smith from Mass General Hospital presented updated data from the phase III 147 trial comparing denosumab to placebo in managing skeletal related events (SREs) and bone metastases-free survival.   Skeletal complications are a major cause of prostate cancer morbidity.

The results were somewhat controversial, however, because while surrogate measures such as delaying time to SREs clearly show a benefit in favour of denosumab, no difference in overall survival was seen over placebo.

To find out whether these measures are clinically meaningful or not, I chatted with Dr Neal Shore, a urologist who is the Medical Director of the Carolina Urologic Research Center in Myrtle Beach, South Carolina as part of the ongoing Making a Difference series of interviews.

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Update on denosumab and SRE’s: data from the 147 trial

By on May 17, 2011

A little over ten years ago, I lost my Father to metastatic prostate cancer, a brave fight that lasted only a few years since he was diagnosed with stage IV disease.   In many ways though, it was a bittersweet moment because while it’s always heartbreaking to lose a parent, it was also a blessing that he was spared of any further pain.   In those days, the only bisphosphonates available in the UK were pamidronate (Aredia) and the awful clodronate.   The urologist managing my Father had no clue about either, so he suffered in silence instead.

I tell this story because, while difficult to discuss, sometimes we forget the importance of supportive care and pain management in improving the quality of life for patients with advanced cancer.

Based on my family’s experience, I can tell you that it makes a huge difference, not just to the patient, but also for other family members.   There is nothing more distressing to see someone in considerable pain from bone destruction and the doctors not doing anything about it because ‘it’s normal for the condition’ or they are considered ‘too old over 65’.   In the end, I suspect many give up the fight because the pain becomes unbearable.

Since my Father’s passing, clinical advances in managing skeletal related events (SREs) and bone pain have thankfully moved on with the approval of another more potent bisphosphonate, zoledronic acid (Zometa) and a RANK-L inhibitor, denosumab (Xgeva). Both of these therapies increase the time to SREs associated with metastases compared to placebo, but what about bone metastases and survival – do they make any difference?

New clinical data now available

This morning at the AUA annual meeting, data was presented by Dr Matthew Smith (Mass General) on the much awaited update on the 147 phase III trial in the late breaking plenary session.   The study compared denosumab (120 mg subcutaneously taken monthly) to placebo.

Overall, in terms of efficacy, denosumab significantly:

– Increased bone metastasis-free survival by a median of 4.2 months compared with placebo ie 29.5 and 25.2 months, respectively (hazard ratio [HR] 0.85; 95% CI: 0.73, 0.98; P=0.028; risk reduction of 15%)

– Delayed time to first bone metastasis compared with placebo (HR 0.84; 95% CI: 0.71, 0.98; P=0.032; risk reduction of 16%)

– Delayed time to symptomatic bone metastasis (HR 0.67; 95% CI: 0.49, 0.92; P=0.01).

However, it wasn’t all good news on the efficacy front though.

Median overall survival was similar between groups (HR 1.01; 95% CI: 0.85, 1.20; P=0.91).

In other words, patients did not live longer when given denosumab therapy compared to placebo.

 

Comparison of side effects

Overall, rates of adverse events (AEs) and serious AEs were generally similar between groups, with two exceptions, namely:

– Yearly cumulative incidence of osteonecrosis of jaw was similar to rates previously reported for monthly denosumab 120 mg (year 1: 1.1%, year 2: 2.9%, year 3: 4.2%), although the overall cumulative rate was 4.6% (n=33).

– Hypocalcemia occurred in 1.7% (n=12) denosumab and 0.3% (n=2) placebo patients.

To put this in context, in the zoledronic acid versus placebo trial, both ONJ and hypocalcemia were lower than that seen in the denosumab study.  According to Medscape Reference, this is not a side effect to be trifled with, since it can cause stroke and cardiopulmonary effects:

“Depending on the cause, unrecognized or poorly treated hypocalcemic emergencies can lead to significant morbidity or death.”

Clearly, some of the effects can be mitigated with calcium and vitamin D supplementation, although some patients, especially though with co-morbidities, may be challenging with adherence and compliance.

A critical question is are surrogate measurements clinically meaningful?

Dr Oliver Sartor raised this issue recently in a Nature publication, essentially challenging whether SRE was clinically meaningful or not, and arguing that better measurements would be a reduction in pain or improvement in the patient’s quality life when considering whether a therapy had an impact or not.

You can find out more about Dr Sartor’s insights in a recent blog post my colleague, Pieter Droppert, posted on Biotech Strategy Blog in the run-up to the AUA meeting.

In order to get to the bottom of this dilemma, I interviewed Dr Neal Shore, a urologist at the Carolina Urologic Research Center, and asked him what he thought of the significance of the data:

“This is a huge milestone in our understanding of the bone microenvironment”

On managing the adverse events versus the improved time to bone-free metastasis, Dr Shore replied,

“I think the risk benefit of preventing a skeletal metastasis versus the small, but albeit statistically real risk of ONJ, far outweighs that risk.”

The interview with Dr Shore will post tomorrow morning as a podcast as part of the Ongoing Making a Difference series – do check back to hear his insights on the 147 trial.

References:

ResearchBlogging.orgSartor, O. (2011). Denosumab in bone-metastatic prostate cancer: known effects on skeletal-related events but unknown effects on quality of life Asian Journal of Andrology DOI: 10.1038/aja.2011.33

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A vlog update on advanced prostate cancer from the AUA 2011 meeting

By on May 16, 2011

After attending numerous basic research and clinical updates at the American Urologic Association (AUA) annual meeting in Washington DC, it is clear that the new and emerging therapies are not going to stop at the three grand crus from 2010.

Recently, abiraterone acetate (Zytiga) was approved, but there are a number of critical issues that need to considered, including:

  1. Sequencing
  2. Combinations
  3. Cost
  4. Patient selection

As we learn more about the molecular mechanisms behind resistance to androgen receptor signaling (up and downstream) and new targets emerge, so it may be possible to improve patient outcomes in castration-resitant prostate cancer.

Here’s a short video update of what I thought was interesting here at the conference:

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