Biotech Strategy Blog

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

Posts tagged ‘rucaparib’

Scaling the ESMO23 ramparts

Scaling the ramparts in Real Madrido

In our last ESMO23 Preview ahead of the live meeting starting on Friday, we highlight another eight targets to watch out for where there will be intriguing data dropping out from Madrid over the weekend.

More than just the data though, is consideration for the implications of the findings and how they can impact a particular tumour landscape.

One thing to note is just because a company highlights what they consider to be positive data doesn’t always mean it is actually so when you look carefully at the small print.

Not surprisingly there are a few examples of this genre at the forthcoming conference…

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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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Going beyond PARP1/2 inhibition with novel approaches

Immune cells and tumour cells can act like a changing kaleidoscope depending on the situation

While we have seen many studies on the mechanisms of primary and acquired resistance to small molecule inhibitors leading to rational combination therapies, our understanding of what’s going on under the hood in response to protein degradation or immunotherapies is much less certain.

In our latest post, we explore how these worlds are now starting to collide and how tumour behavior at the time of resistance can better inform translational studies as well as future clinical combinations.

While there have been numerous studies emerging on the dual IO-IO front, let’s not forget there are still many opportunities to explore synergies with small molecule agents to address mechanisms of resistance…

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Making your mind up

Time for some commentary and review of ESMO highlights and lowlights from Paris

One of the fascinating aspects of the PARP inhibitor niche is how often the results across several different company trials have gone the same way more often than not.

This has been a rather unusual streak, let’s face it.

At some point I was half expecting the wheels to fall off the wagon and the trend to be bucked, to much consternation from outside observers.

It’s already starting to happen, although perhaps not in the way we might have anticipated.

After all, you can’t enroll patients willy nilly and expect to see a positive result every time because patient selection can and does matter over the long run.

Here, we discuss some of the emerging controversies coming out from ESMO…

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Pulling a rabbit out of a hat

It’s time to tackle some controversies in advanced prostate cancer and look at exactly who’s pulling a rabbit out of a hat?

At ASCO GU we saw new phase 3 data from the 1L metastatic castrate resistant prostate cancer (mCRPC) setting with very different results produced for olaparib and niraparib, generating quite a bit of debate.

Here we explore half a dozen key issues in the context of both trials and look under the skin at the important subtleties and nuances to think about…

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Olaparib drives earlier and deeper responses in mCRPC

With two oncology data drops running this week in the ASCO Plenary session plus the GU sympoisum, it’s time to switch our attention from cell therapy novelties to new developments in targeted therapies.

In this discussion, we take a look at an important phase 3 trial readout being presented this week in metastatic castration resistant prostate cancer (mCRPC).

For far too long the GU oncologist’s choices were pretty much limited to androgen receptor (AR) antagonists such as enzalutamide and abiraterone and chemotherapy (docetaxel and cabazitaxel).

Then along came PARP inhibitors such as olaparib, rucaparib, and more recently niraparib, largely limited to men with homologous recombination repair deficiencies who had received prior therapy, with the first two receiving full or accelerated approval in first half of 2020 on the basis of the PROfound and TRITON2 studies, respectively.

The third PARPi is further behind the others, finally just publishing their phase 2 monotherapy data from GALAHAD earlier this month.

Now there’s a new phase 3 data readout to explore and consider in the context of earlier in the disease setting…

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Endless DDR changes and how we are going beyond PARP inhibitors

There are at seemingly endless genes associated with genomic instability and the development of cancer – there are at least 450 genes associated with DNA Damage Repair (DDR) alone, for example.

This means it is, perhaps, not at all surprising these can not only induce significant changes in various tumours, but they also might have deeper interactions between them as well, many of which we may not yet know about.

Just as we have seen some success with PARP inhibitors in patients with BRCA loss of function, so too are companies seeking to exploit additional vulnerabilities by targeting the achilles heel with other paired approaches such as ATR inhibitors in cancers where there is ATM loss of function.

There has been a raft of data in this niche from several agents in this class so it’s time to turn our attention to reviewing what we learned from the many subtleties and nuances that inevitably abound in this DDR subniche, including recent data presented by Repare Therapeutics at the AACR-NCI-EORTC meeting…

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Coming back full circle

Where are we headed in the DDR niche?

The dog days of summer always seem to portend a mix of sunny days and stormy skies ahead…

In this latest report we cover important issues around homologous repair deficiency (HRD), new replication stress targets, as well as how both analysis and assays are being developed to meet the evolving needs of the field.

There is much nuance going on behind the scenes, which will be important to keep up to date with, including some tumour types not previously associated with DNA damage repair, something we highlight in this post.

These findings might have implications for future regimens and may explain some of the undetected mechanisms of resistance we are seeing in existing trials being presented at ESMO or the forthcoming Molecular Targets (TRIPLE) meeting.

There are also diagnostic developments to think about, not just therapeutic ones…

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Tooting the DDR horn

Every year the sweet spot sandwiched between AACR and ASCO comes around all to quickly, as we’re wrapping up interviews conducted at one and preparing the previews for the other, never mind ESMO Breast, AAI, and ASGCT all coming in May as well.

Cambridge Botanical Gardens

This year is no different and I’m delighted to say they segue rather nicely for once!

It’s hard to believe we’ve been writing about DNA damage repair and PARP inhibitors since 2008/2009 or so, and still this topic just keeps growing and growing!

We’ve certainly come a long way since those early days and now the broader DDR niche is also expanding as more targets are identified and evaluated, both in animal models as well as the clinic.

This list will also increase as CRISPR screens continue to identify synthetically lethal targets – some will be useful, others will fall by the wayside due to lack of efficacy or poor tolerability. Finding a balance between the two will therefore be a big key to success.

In this post we’re going to start with an update on the PARP1/2 inhibitors then catch up on data from other DDR family targets and finally explore a pipeline discussion with an industry expert who is well versed in the DDR field.

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AACR21 Preview 5 Promising new developments in the PARP field and beyond

Imagine the DDR pathway as a mass of many different notes and targets all interconnected…

We’re on our fifth AACR Preview already this year and there’s plenty more science and clinical topics to cover yet as we go through the emerging topics up on deck.

In this latest update we take a look at the growing field of DNA damage repair – not just old targets, but a raft of emerging ones too, some of which are still in early preclinical development while others are in early phase 1 trials.

We also have some expert commentary on some of these new targets – what stands out, what’s validated and just as importantly, what’s not?

It’s time to get to the centre of things in PARP-land…

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