Biotech Strategy Blog

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

Posts tagged ‘Prostate Cancer’

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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Cut and run

Sometimes it’s the unexpected or quirky changes that stand out

While many observers have almost exclusively focused on protein degradation in the context of modern chemical proximity approaches, this isn’t the only possibility when using a bifunctional small molecule.

Indeed, I would argue some of the most creative ideas we are seeing coming out of late may well turn out to be unexpected standouts in future clinical trials.

Yet their goal is a very different one from what we’ve seen from the majority in the clinic.

In this latest example of the genre, we turn our attention to an area where drug hunters have struggled to find solutions for, despite the challenge being a commonplace issue for many oncologists in the clinic…

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Changing of the guard

A frequent challenge in oncology R&D is the fast paced nature of pipeline development such that there’s always something cool or new coming along nipping at the heels of those further ahead in clinical development coupled with the changing of the broader landscape before you even get to market.

What this means is companies with agents in phase 2 development can frequently feel rather squeezed between the two extremes.

This can lead to a lot of pondering on whether they will have enough innovation to make an impact on whatever are the favoured approaches by the time they might get to market, while at the same time offering sufficient protection against the novel compounds coming along behind.  Obviously no one drug is perfect and each will have their own achilles heels, to add to the mix and uncertainty.

For some time now there hasn’t been much in the form of new approaches in prostate cancer beyond the myriad of androgen receptor antagonists in various treatment niches plus the PARP inhibitors in a select population of men with BRCA mutations… what then?

A big question targeted therapies often have to address is their impressive initial response rates and PFS based on RECIST measurements don’t always translate into people living longer, as measured by overall survival.  No drug is without toxicities either, which means these need to be factored into the final clinical decision making and can make or break early uptake more than initially realised.

In our latest review we highlight some examples of where the field might be headed next (or not), based on some new preclinical and clinical data presented…

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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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Advent of a new era in advanced prostate cancer treatment

ASCO21 – we may not be in Chicago, but this year’s virtual ASCO annual meeting does not disappoint in terms of a series of important clinical data emerging, which have the potential to change the cancer treatment landscape.

The results of the Novartis sponsored VISION trial with 177Lu-PSMA–617 in metastatic castration resistant prostate cancer (mCRPC) being presented in Sunday’s plenary session opens the door to a new line of treatment options which can only be of benefit to men with refractory disease.

Whether 177Lu-PSMA–617 will end up being the best radioligand therapy targeting PSMA (Prostate Specific Membrane Antigen) remains to be seen, but the company are to be congratulated in breaking new ground, with a clear path to market strategy enabling them to be the first to market in this indication.

Radioligand therapy combines a radioisotope that causes DNA damage, leading to replication stress or cell death with a tumour targeting compound. It offers a lot of potential in many cancer disease settings and is a topic we expect to hear more about as other companies follow Novartis’ lead and more knowledge is gained about optimal patient selection, dosing, sequencing and combination strategies.

Is it Mardi Gras time at ASCO?

For an expert perspective on what the VISION trial means in the context of the evolving prostate cancer landscape, BSB spoke with Dr Oliver Sartor (Tulane), who participated in the 177Lu-PSMA–617 trial.

Dr Oliver Sartor is a global prostate cancer expert who we’ve had the pleasure to talk with a few times over the years. He’s a professor at Tulane University in New Orleans and Medical Director of the Tulane Cancer Center.

He cheerfully told BSB:

“This is an exciting development with the VISION trial and I think it changes the landscape, even though it is sort of at the end of therapy – these patients were pretty heavily pre-treated.

I think it has implications as we look over the overall landscape for a whole variety of patients, and of course, this therapy is likely to move earlier and trials are already designed to help it move earlier. So I’m excited about the progress for a PSMA targeted therapy with Lutetium–177 and I think it is going to have implications for years to come.”

BSB subscribers can read more of Dr Sartor’s perspective on the VISION trial and emerging prostate cancer landscape, subscribers can log-in or you can click to read our ASCO21 coverage.

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A phoenix rises from the ashes

A phoenix rises from the ashesResilience in purpose and openess in strategic direction are key dual features in the DNA of strong biotechs which succeed in the long run and live to survive the roller coaster ride that is oncology R&D.

Setbacks are to be expected, but what matters more is not that they happen, but the mettle and toughness to deal with them over time.

There is no doubt Clovis Oncology encountered a major setback with the abandonment of rociletinib in lung cancer, while the rise of PARP inhibitors meant they were well placed with the rucaparib development.

Beyond these events, what next?

It’s time to take a bigger picture look at what’s happening with the pipeline and where they might be heading since there could be some surprises in store…

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Important learnings from ESMO20

A typical scene from ESMO 2019

Not in Madrid – Is it really only a year ago many of us were frantically dashing around at ESMO last year navigating crowded corridors, long queues for coffee, hunting down the last empty seat in jam packed halls, not to mention feeling the anticipation build for key data being presented in the Presidential sessions?

There are undoubtedly many advantages to virtual digital meetings, aside from the broader access for more people it provides and being able to see the slides unimpeded, yet it must be confessed the things I miss the most are the social interactions and catching up with people and their lives, however brief a moment it may be amongst the hurly burly of 20,000 other souls.

The cultural things we take for granted are often the very essence of what we miss most when they’re no longer obtainable.

Who truly would have guessed our world could be completely upended by the unexpected events of a global pandemic since then? In some ways, it has changed our perception of both time and space.

We have also seen some surprising changes in the fortunes of various clinical trials; some completely rational and predictable, others quite the opposite, as we learned yesterday in a very topsy turvy kind of way.

It’s time to discuss and review the highlights – and lowlights – from ESMO20 Sunday in part 2 of our daily coverage…

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New developments in Genitourinary cancers

San Francisco!

San Francisco – It’s time to switch horses for some the latest conference coverage and explore some important new findings emerging from the genitourinary world of bladder, prostate, and renal cell cancers at the ASCOGU specialist meeting held late last week.

Not that many years ago, much of this niche was dominated by numerous updates in prostate cancer, with little good cheer to write about on the other two cancers – how things have changed in such a short time!

This year there’s plenty going on in all three categories, I’m pleased to say.

Here we focus on several important trials or targets and explain why they matter and what’s significant about the findings…

Some of the agents or trials selected here are likely to receive more attention going forward as more data become available, so it behooves us to set the scene now.

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ESMO19 Day 4 Highlights including the PROfound trial in advanced prostate cancer

Gah, if only we hadn’t enrolled allcomers in our study, the differences would have been so much bigger!

Barcelona – This is the day when many people get absolutely walloped by exhaustion at ESMO even after three double espressos – if you’re still going strong then I commend your stamina and fortitude!

This is a big day for several companies with important phase 3 trial readouts due to be presented at the conference today.

One in particular is the phase 3 PROfound trial exploring the role of the PARP inhibitor, olaparib, in HRD+ advanced prostate cancer.

Beyond the top line findings (the PFS endpoint was met) there are a LOT of subtleties and nuances to consider so we have an analysis to share of some of the pitfalls and potential issues that may be missed in the hurly burly and noise.

Are you ready?

There’s a lot to think about today, not just in PROfound, but also quite a few other studies have been put under the microscope too.

Here we go unto the breach, my friends…

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ESMO19 Preview 2 – Targeting Synthetic Lethality and Immune Response in GU malignancies

We’ve been writing about PARP inhibitors since 2006!  Who knew this target would have multiple legs over a dozen years on?

Barcelona

In this post we’re taking a look at some of the noteworthy presentations at ESMO19 around targeting DNA damage repair (DDR) and how they act through synthetic lethality and/or the generation of immune response to kill cancer cells in GU cancers.

It’s a fascinating area where we are seeing convergence between immunotherapy and genomic instability, one of the hallmarks of cancer.

The abstracts for ESMO19 are not yet available, so in this post we’re only providing context and setting the scene for some of the presentations we are looking forward to, as well as raising some key questions that we hope will be answered in Barcelona.

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