Biotech Strategy Blog

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

Posts tagged ‘CRPC’

Every once in a while a completely new modality comes along, which turns things on their head and changes how we think about cancer drug development.

The first chemotherapy, the first TKI, the first monoclonal antibody or bispecific antibody… the list goes on.

Each one creates a new race and bunch of companies and molecules quickly follow the trendsetter.

How about the first protein degrader to show initial evidence of clinical activity in men with a particular type of cancer?

This is exactly what Arvinas have done with their novel PROTAC molecule, ARV–110, in men with advanced metastatic castration-resistant prostate cancer who have received prior hormonal therapy.

What can we learn from the data due to be presented at ASCO and from what lens of the kaleidoscope should we be really be looking at? To find out more, I spoke to an expert in this niche, the scientist who developed the technology, Dr Craig Crews.

What he had to say and how he got there is well worth listening to. I doubt doubt he quietened a few sceptical researchers along the way who likely thought it wasn’t possible to do in patients having heard a few of them in Q&A sessions at various conferences over the last five years. One of them (who will remain nameless) when asked what he thought of the idea actually scoffed at me in a coffee break, “It’s a preposterous idea – it’s fine in mice I suppose, but it’ll never be done in patients, mark my words!”

*Coughs*

During my convivial chat with Dr Crews, I was remembering the moment from the past and wondering what he might be thinking now… to the brave and creative scientists go the spoils of victory.

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In today’s post we answer some reader mailbag questions pertaining to targeting BET/bromodomain inhibitors and what we’ve learned since our original landscape review from early 2016 when they were an emerging new class in the oncology R&D space – how time flies!

Is it time-up for the bromodomain class?

Of course, as usually happens in the targeted therapy space we see a glut of pan inhibitors trying to block everything in sight to a greater or lesser degree… we’ve see this with BRAF, FGFR, PI3K, and even KRAS inhibitors, as well as numerous others, yet these rarely turn out to be the bees knees we’re secretly looking for. Bromodomains, I have long argued, were ripe to fall in this category as well.

Instead, it is better to patiently wait for the next generation molecules where they are much more selective in their actions and matched to the tumour target we are looking to hit.

Think about the BRAFV600E vs. pan BRAF inhibitors or KRASG12C/D vs. pan KRAS inhibitors, for example, or even FGFR2 or FGFR3 vs. pan FGFR inhibitors.

The same evolution may possibly happen in the BET/bromodomain space too.

The first generation of agents seemed to hit everything – BRD1, 2, 3, 4, and often BET as well. They suffered, however, with weak efficacy largely driven by challenges with the on-target, off-tumour effects that necessarily impact the therapeutic window.

Now we are starting to learn from a more focused approach with these agents. Four years on from our original landscape review, what’s hot and what’s not? Who’s in and who’s out? In terms of the magic roundabout of oncology R&D, are there any new gems we should eagerly be watching out for?

The short answer is yes… but what are they and who owns them?

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It’s a Bank Holiday weekend on both sides of the pond, which is always a good excuse for some shorter snippets as everyone will be enjoying the break outside, weather permitting!

In our latest Preview series, we address some pertinent questions that have come in from BSB readers on several topics in between AACR and ASCO, including tumour mutation burden (TMB), the PACIFIC trial, monalizumab, renal cell carcinoma (RCC) and castrate resistant prostate cancer (CRPC).

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The abstract has just been published for the phase 3 PROSPER trial to be presented later this week at ASCO GU in San Francisco (#GU18).

@Daniel_J_George

PROSPER: A phase 3, randomized, double-blind, placebo (PBO)- controlled study of enzalutamide (ENZA) in men with nonmetastatic castration resistant prostate cancer (M0 CRPC).

Earlier today Dr Daniel George (pictured), one of the investigators, kindly spoke to BSB about how he interprets the trial data and what it may mean for the treatment of prostate cancer.

Dr George (@Daniel_J_George) is Professor of Medicine and Surgery, and Director of Genitourinary Oncology at the Duke Cancer Institute.

Should men with non-metastatic CRPC receive enzalutamide in order to PROSPER?

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Medivation-LogoThere’s nothing better than seeing good news in the early morning email alerts I have set up on cancer research!

 

astellas-logo-no-sloganToday, it was the turn of Astellas and Medivation to announce the results of the TERRAIN study, which is a primarily European phase 2 trial that began in March 2011 in the prechemotherapy setting for castrate resistant prostate cancer (CRPC). The trial met its primary endpoint of progression free survival (PFS).

 

Why is this an important landmark in CRPC and what does the initial data show?

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Sometimes timing can be amusing when writing up data and conferences. Yesterday, while writing about the immuno-oncology developments in renal cell cancer (RCC), I was putting a table of the trials together and absent mindedly noticed that Merck didn’t have much going in this indication compared to BMS and Roche/Genentech.

Oddly, the company fixed that this morning with their announcement that they are expanding their combinations and collaborations for the anti-PD–1 antibody, MK–3475. One of the new trials includes a partnership with Pfizer for axitinib (Inlyta), enabling them to study a PD–1 + VEGF combination in RCC. The table in yesterday’s thought piece has now been updated to include this trial, although it is in the planning stage at present.

Today, I want to switch horses a little bit and talk about another immuno-oncology therapy, namely, ipilimumab (Yervoy).  Dr Charles Drake (Johns Hopkins) presented an update on the post chemotherapy trial (CA184–083) in CRPC at ASCO GU this weekend, which we wrote about from ESMO last Fall when the data was first presented (see here).  What’s interesting is that the trial, although negative, only just missed its endpoint.

Last week I came across some interesting new developments relating to ipilimumab that are well worth discussing here, particularly in relation to biomarkers, as they may have significant implications for the drug clinically.

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$EXEL Share Price Jan 6 2014The share price of Exelixis ($EXEL) is starting a run-up (after months in the doldrums) in advance of anticipated results from the COMET-1 phase 3 trial in metastatic castrate resistant prostate cancer (mCRPC) for cabozantinib (Cometriq, formerly XL184).

Cabozantinib is a small molecule tyrosine kinase inhibitor of c-Met and VEGFR2. It has been shown to significantly improve bone scans and decrease pain, but the $64,000 questions are will patients taking it live longer and feel better?

The answers will come from the COMET-1 trial that has a primary end point of overall survival (OS). It’s a placebo-controlled trial of 960 men with advanced prostate cancer randomly assigned to cabozantinib 60mg (n=640) or prednisone (5mg twice daily) (NCT01605227) who have disease progression after treatment with docetaxel chemotherapy and abiraterone (Zytiga) or enzalutamide (Xtandi).

We previously predicted this trial would be a miss, but did it turn out that way and why?

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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.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

 

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

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

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

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