Biotech Strategy Blog

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

Posts tagged ‘Advanced Prostate Cancer’

Coit Tower San FranciscoAt the recent ASCO 2016 Genitourinary Cancers Symposium (ASCO GU) that took place in San Francisco the week before the JP Morgan Healthcare Conference (JPM), one of the noteworthy presentations was on a novel target for men with advanced prostate cancer.

While JPM may have been a “dud” for many, several companies did take the opportunity to update and discuss their corporate strategy going into 2016, which gave a surprising amount to comment on in our 3 blog posts from the meeting: JPM Day 1, JPM Day 2, JPM Day 3.

In this post we look at the “take homes” from the ASCO GU presentation, and what looks like it could be a new race to market.

It’s good to see novel targets for men with advanced prostate cancer, and potential new treatment options on the horizon!

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At the ASCO GU meeting in January, Dr Thomas Beer presented the initial data for the PREVAIL trial, which explored enzalutamide (Xtandi) in castrate resistant prostate cancer (CRPC) prior to chemotherapy. Reactions to the data were mixed with many analysts, perhaps naively, focusing on the significant temporal survival benefit (2 months) rather than the 29% hazard ratio, which demonstrates the magnitude in the reduction in the risk of death over the control arm.

This weekend at the American Urological Association (AUA) meeting in Orlando, Dr Christopher Evans (UC Davis), presented the updated data, including the survival curves and a subset analysis for visceral and non-visceral disease. He focused on the clinical benefits that were clinically meaningful to the urology audience.

I have to say that the data shown was both compelling and impressive to me.

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Amsterdam – Earlier today, I had the great pleasure at the European Cancer Congress to interview Oliver Sartor, MD, the Piltz Professor of Cancer Research in the medicine and urology departments of Tulane School of Medicine in New Orleans, LA.

A recognized expert in prostate cancer, Dr Sartor was gracious enough to give me an impromptu interview in the poster hall at ECCO 2013 and share his thoughts about the prostate cancer clinical data presented in Amsterdam.

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Subscribers should see a SoundCloud below that they can click on to listen to the interview with Dr Sartor. If you don’t see it, send me an email and I will provide a private URL link that will take you direct to SoundCloud.

Takeda’s orteronel (formerly known as TAK-700) may be on its way to “dog drug heaven” after an interim analysis of the ECM-PC 5 phase 3 clinical trial showed that men with advanced prostate cancer taking the drug did not live significantly longer (HR 0.894, p=0.226) than those taking an inactive placebo.  Here’s a link to the Takeda press release.

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AZD3514 is a novel Selective Androgen Receptor Down-Regulating Drug (SARD) that showed early preclinical promise for the treatment of Castration-Resistant Prostate Cancer (CRPC).

However the development of this drug in advanced prostate cancer has been terminated by AstraZeneca according to Dr Aurelius Omlin, a Clinical Research Fellow at The Royal Marsden Hospital who presented clinical data on AZD3514 at the 2013 annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago.

I previously wrote about the promising preclinical data for AZD3514 presented by Sarah Loddick at the 2012 annual meeting of the American Association for Cancer Research (AACR) and sometimes drugs when they transition to the clinic just don’t live up to their promise.

That’s what happened here, and it reminds us that testing of drugs on human volunteers remains a key part of drug development despite the inherent risks. (See my post on the TLS deaths on the AbbVie/Genentech ABT-199 CLL dose finding trial)

AZD3514 ASCO 2013 PresentationThe results from a first-in-human clinical trial with in men with CRPC were presented by Dr Omlin at ASCO 2013 (abstract 4511). In his oral presentation, he first noted that:

“AZD3514 is a first-in-class, non-steroidal small molecule androgen receptor (AR) down-regulator that inhibits nuclear AR translocation and results in proteasomal AR protein degradation.”

The phase 1 clinical trial to assess safety and tolerability explored doses ranging from 100mg once daily (OD) to 1000mg OD in capsule formulation, and from 1000mg OD to 2000mg taken twice daily (BID) in tablet formulation. A pretty comprehensive range, but……

“Tolerability of AZD3514 was problematic,” said Omlin. “80% of patients had Grade 1-2 Nausea (n=39 out of 49) and 49% Grade 1-2 Vomiting (n=24 out of 49).”  Additionally, grade 1-2 thrombocytopenia was seen in 33% of patients.  There was no dose limiting toxicity reported.

What killed it for AZD3514 was the fact that according to Omlin,

“Nausea and vomiting were characteristic from the very first dose level starting about 30-60 minutes after dosing and lasting for several hours thereafter.”

However, the drug did show activity in CRPC patients with several patients showing PSA declines including one patient with prior abiraterone exposure.  Two patients with soft tissue disease had confirmed responses according to Recist 1.1. There was also evidence of clinical activity from changes in the number of circulating tumor cells.

Industry analyst, David Miller (@BiotechStockRsr) commented on Twitter, while watching the presentation, that he thought it hard to see the drug progressing in development, and he turned out to be correct:

Dr Omlin concluded his presentation by stating that, “the development of this compound by AstraZeneca as a selective androgen receptor down-regulator in mCRPC has been terminated.”

Sometimes promising preclinical data just doesn’t hold up when it moves into human clinical trials. Another AstraZeneca drug with preclinical promise has gone to what Sally Church, PhD (@MaverickNY) refers to as “dog drug heaven.”

At the 2012 annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago, Oliver Sartor, Professor of Cancer Research and Medical Director of the Tulane Cancer Center in New Orleans told attendees in the educational session on castration-resistant prostate cancer (CRPC) that he was tired of being asked the question of what is the optimal sequence for new advanced prostate cancer drugs?

ASCO 2012 CRPC Prostate Cancer Education SessionThere is “No data,” Sartor told the ASCO 2012 audience. As a result he recommended the use of less toxic therapies first and that patients be involved in the decision making. Not quite the guidance the audience perhaps hoped for.

Sartor is, however, correct that we don’t yet have the data – the clinical trials have yet to be done that will answer the question of what is the optimal sequencing of prostate cancer drugs?

The approval of abiraterone acetate (Zytiga®) for the treatment of men with advanced prostate cancer, post chemotherapy, and the expected approval of enzalutamide (formerly MDV3100) and radium-223 (Alpharadin) have focused attention on sequencing and combination options.

A poster at ASCO 2012 showed that cross resistance may occur between abiraterone and enzalutamide, suggesting that if resistance to one develops it may lower the efficacy to the other if given subsequently. More data and research is needed to validate this finding and understand how resistance develops.

Reciprocal feedback between the PI3-Kinase and androgen receptor (AR) signaling pathways means that blocking the androgen receptor may stimulate the PI3K pathway and vice versa, leading to the tumor trying to ensure its survival. This is particularly important in prostate cancers that have the PTEN tumor suppressor gene, the result is that the targeting of both PI3K and the AR to avoid crosstalk may be required.

The scientific rationale for combining enzalutamide with a PI3-kinase inhibitor was discussed on Pharma Strategy Blog in Sally Church’s video from the 2011 American Urological Association annual meeting. Clinical trials are being planned to investigate the use of PI3-kinase inhibitors in prostate cancer.

I have written more from ASCO 2012 about the emerging challenges in prostate cancer drug development in a guest post published on Xconomy.  Many thanks to Luke Timmerman, National Biotech Editor, for the opportunity to contribute.

Hopefully, there will be more insights available at ESMO 2012 later this year and at ASCO next year on prostate cancer drug resistance, optimal sequencing and the benefits that combinations therapies may offer.

This is part 2 of my interview with Dr Maha Hussain, Professor of Medical Oncology at the University of Michigan.  You can read part 1 about cabozantinib and pain here.

Cabozantinib-Prostate-Cancer-Bone-Effect

At the 2011 ASCO annual meeting, Dr Hussain presented data from a non-randomized phase 2 trial with cabozantinib that showed dramatic improvements in bone scans before and after treatment.

Bones are living tissues that are constantly being remade, a dynamic process that involves formation of new bone and taking up of old bone, a process known as bone resorption.  Cancer cells can interfere with bone remodeling, resulting in increased new bone formation (osteoblastic response) or excessive bone resorption (osteoclastic response).

Bone scans involve the injection of radioactive tracers such as technetium-99m-MDP. In simple terms, the radioactive material detects bone turnover and areas of high bone metabolism.  These show up as darker “hot spots” where the tracers accumulate.

Bone scans have poor specificity because tumors, fractures and infection all lead to hot spots. Also, not all tumors or lesions are detected by a bone scan.  Bone scans have a sensitivity of around 62-89%.

At the 2011 Society for Translational Oncology Prostate Cancer Symposium, Professor Johann de Bono (The Institute for Cancer Research) noted that bone scans do not accurately reflect the activity of the disease in men with prostate cancer.

This raises the question as to what we should conclude from the bone scans seen with cabozantinib.  I put this question to Professor Hussain.

BSB: What is the significance of the bone scans that we see and what should we interpret from them given that bone scans don’t accurately reflect the disease?

Dr Hussain: I will refer you back to my presentation at ASCO originally and my recent AACR presentation.

I have specifically put a slide (together) to address, is what we are seeing a fluke, a function of a technique issue because you are targeting the osteoblasts?  Consequently if you inhibit osteoblastic function, you are not going to see much changes on the scan, or is there more too it?

Dr-Maha-Hussain-ASCO-2011-Cabozantinib-Presentation

The specific slide actually puts in columns the (percentage of) patients who had a partial or a complete resolution on the bone scan, versus those who had stable or progressive disease, and then matches it with other evidence of an anti-tumor effect as in target lesion regressions, progression free survival at I think the 6 month mark if I recall correctly, as in the pain improvement, narcotic use.

Recognizing that by the way the pain and narcotic use, both of these were post-hoc assessments that were done.  Once we saw the observation, the sponsor went back and began asking all the investigators to record these things.  Clearly, the ALK phosph going down, the bone turnover markers going down.

The short audio clip below expands on Dr Hussain’s viewpoint about cabozantinib and bone. Click here if you can’t see the SoundCloud audio player.

Dr Hussain’s conclusion is interesting from a marketing strategy perspective.  She does not position cabozantinib as a bone targeted drug such as Xgeva or a bone targeted radiopharmaceutical such as Alpharadin.  Instead, her view is that cabozantinib should be developed as a “prostate cancer specific drug that does have the added advantage of significant anti-tumor effect in the bone” ie an anti-cancer tyrosine kinase inhibitor (TKI).

This is at odds with how Exelixis appear to be positioning it.  The corporate presentation at the Cowen Annual Healthcare Conference on March 6, 2012 had a strong focus on bone metastases: “Cabozantinib demonstrates unique ability to resolve bone metastases and decrease bone pain in CRPC,” one slide said.

If Dr Hussain is correct and we should consider cabozantinib as a prostate cancer specific drug, then it will need to compete on endpoints with other drugs that have shown an impact on overall survival.

Cabozantinib will likely not obtain regulatory approval on the basis of the bone scans, whatever they may show.

Without demonstrating a significant effect on overall survival, it’s hard to believe that cabozantinib will be able to compete effectively in what is fast becoming a very competitive prostate cancer market.

The final installment of the Biotech Strategy Blog interview with Dr Hussain will cover her perspective on the mechanism of action of cabozantinb, and where the drug, theoretically, might be expected to have most impact in prostate cancer.

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Maha Hussain MB ChB is Professor of Medical Oncology at the University of Michigan.  She is an international expert into genitourinary malignancies with a focus on clinical research into prostate and bladder cancer.

Cabozantinib is a new drug in development by Exelixis for multiple indications.  It captured a lot of attention at the ASCO 2011 annual meeting last year, when Dr Hussain presented data from a phase 2 prostate cancer trial that showed a dramatic improvement in bone scans and pain reduction in those men receiving it.

Unlike other new prostate cancer drugs such as abiraterone (Zytiga) or MDV3100 that target the androgen receptor, cabozantinib is a multi-kinase inhibitor of MET and VEGFR.  It has both an anti-tumor effect and an effect on bone metabolism.

At the AACR Advances in Prostate Cancer Research conference last month, chaired by Charles Sawyers (MSKCC) and Arul Chinnayan (Michigan), Dr Hussain gave a presentation on “Cabozantinib (XL-184) and prostate cancer: preclinical and clinical profile of a novel agent.”

I was privileged to have the opportunity to interview Dr Hussain by phone recently and obtain her insight into cabozantinib as a potential new treatment for prostate cancer.

We covered a lot of ground, too much for one blog post, so I’ve broken down the interview into segments that I will be posting separately.

Cabozantinib & Pain

As many readers will be aware, one of the dramatic results presented at ASCO last year, was the impact that cabozantinib had on pain.

AACR-Molecular-Targets-2011-Cabozantinib-Pain-DataAt the AACR Molecular Targets meeting in San Francisco last November, further pain data was presented by Howard Scher’s group at Memorial Sloan-Kettering Cancer Center. They showed in a non-randomized phase 2 trial that:

Cabozantinib treatment resulted in high rates of pain improvement and analgesic reduction or discontinuation in patients with moderate to severe pain at baseline

–  Rapid and durable pain relief

–  Pain relief observed regardless of prior lines of therapy

–  Improvement in pain accompanied by reduced interference with sleep and daily activity

Exelixis has since moved forward with clinical trials focusing on prostate cancer pain.

Pain response is the primary outcome in the phase III trial (COMET-2) of cabozantinib (XL184) Versus Mitoxantrone Plus Prednisone in Men With Previously Treated Symptomatic Castration-resistant Prostate Cancer (COMET-2 trial formerly known as XL184-306). Overall survival is a secondary endpoint.

The challenge with using pain as a primary endpoint is that all the advanced prostate cancer drugs that have recently been approved by the FDA such as cabazitaxel (Jevtana), abiraterone (Zytiga), and those for whom approval is expected, such as MDV3100 and radium-223 (Alpharadin), have all shown an improvement in overall survival.

I was, therefore, interested to hear Dr Hussain’s perspective on cabozantinib and its effect on pain in prostate cancer.

BSB: Can pain be a surrogate for survival that regulatory agencies might accept?

Dr Hussain: Honestly, I am not the expert on what the regulatory agencies will do. I know what they have done and I would say that pain has been an indication for regulatory approval of prostate cancer. That’s a long story, it’s an old story. Mitoxantrone was approved based on pain, so I don’t think that is going to be an issue.

Whether it is a surrogate for survival remains to be seen, and to be honest with you, I think that it may not be if you are really using it in far advanced cancer. As we have seen with mitoxantrone, it didn’t seem to make an impact on survival and it is really more about disease progression and pain and quality of life type issues. 

I am not aware of a trial that has been done with a primary endpoint being pain, and another key primary endpoint or a secondary endpoint being survival, that has been positive.  Having said that, I think in my view, it is a mistake to just focus on the pain. 

Pain, as far as I can tell from our experience and others, it’s very late in the setting of the disease by a nowadays standard. I would argue that using this drug as a pain only type drug, you could do it cheaper and less toxic with other agents, with morphine for example. 

My point here is, I go back and say to focus it on pain only, my average patient is interested in living longer, not just in controlling their pain. 

You can hear more about this in the SoundCloud audio clip below.  Prostate cancer patients are not just interested in “how will this drug make me feel,” but also “will I live longer?”  Click here if you can’t see the audio file.

Dr Hussain: My point is in a perfect world if the drug delivers, the importance is going to be a totality of effect, that is prolonging life and improving quality of life overall.

BSB: Thank you

The next installment of the Biotech Strategy Blog interview with Dr Hussain will focus on the clinical significance of the dramatic bone scans seen with cabozantinib.

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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.

EAU-2012-Delegates-Waiting-to-enter-Advanced-Prostate-Cancer-Poster-SessionThere 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-phase-2-results-presented-at-EAU-Paris-Congress-2012Orteronel (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.

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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