Biotech Strategy Blog

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

Posts tagged ‘CRPC’

The dirty little secret biotechs don’t tell you

Do not feed the alligators is a common sign seen in the hammock areas of Florida where brackish fresh water abounds.

It has always amazed me people might even consider getting close enough to see them since common sense would tell you to beat a hasty and instant retreat from those big toothy maws!

Similarly in biotechland sometimes there are warning signs aplenty and yet people still ignore them, preferring to focus on the good.

Today’s story is a cautionary one where, much like with those “Do not feed the alligators” signs, researchers and investors might be wiser to heed certain warnings rather than focusing solely on what initially appears to be positive data.

Ignore the warning signs at your peril…

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Playing with fire

Are we playing with fire – again?

A few years ago, Dr Philippe Armand at Dana Farber used this very colourful phrase accompanied by ‘rip roaring toxicities’ when describing autoimmune type reactions his institution had seen in patients with hematologic malignancies who had received prior allo SCT (see more here).

Now we’re starting to see more evidence emerge for improved activity with next generation bispecifics accompanied by lethalities.

Finding the balance between the two is proving to be something akin to a tightrope across the Niagara Falls without a safety net.

With so many runners and riders in the IO niche, it’s often hard to tell who will be the winner

Checkpoint blockade, CAR-T cells and fusion proteins haven’t been the only ones to struggle with this challenge, since bispecifics are also an immunotherapy approach capable of inducing some potent, if unwanted immune effects.

Here we look at the challenge in the bispecific arena with a focus on some recent events…

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A novel target to explore in prostate cancer

Source: AlphaFold

Our latest post discusses key topics around the novel target shown on the right – brownie points to anyone who can guess which one it is!

Aside from having a lot of fun exploring protein targets with DeepMind’s AlphaFold tool, they also help illustrate something important, which is the degree of confidence around the various aspects from dark blue for high confidence and yellow for very low confidence predictions.

Tau, if you haven’t yet seen it, is truly a hot mess compared to today’s choice!

While there is always the concern about whether a particular protein is a marker or a valid oncogene target, we have to start somewhere and see where the clinical trials take us because some modalities might turn out to be much better ways of approaching the problem of ‘druggability’ than others.

I went into this foray with an open mind and some degree of hope because let’s face it, we need more new agents against novel targets than we do of yet more me-toos against old targets…

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When IO, targeted therapy and oncogene worlds collide

Rodin’s The Thinker sculpture   Source: Wikimedia Commons

Recently, I have been pondering a raft of clinical and translational data we have seen emerge across multiple virtual conferences from several different categories of therapies such as checkpoint blockade, targeted therapies, PARP inhibition, epigenetics, and even mathematics.

Many people tend to look at these disparate categories and see them as quite different therapeutic options, but lately I have began to wonder if they are in fact much more inextricably linked than seems obvious at first glance?

This turned into a broader strategic post about advanced solid tumours and how we might think a little differently about underlying concepts and conceptual frameworks…

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Is the Arvinas PROTAC Proof of the Pudding?

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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Time is ticking on the bromodomain landscape

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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ASCO18 Reader Q&A

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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Go Forth and PROSPER

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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Enzalutamide beats bicalutamide in advanced prostate cancer

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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Update on immuno-oncology and biomarkers of response

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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