Biotech Strategy Blog

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

Posts tagged ‘PARP inhibitors’

Recently, PARP inhibitors have been back in the news for several reasons, including the publication of the olaparib (AstraZenca/Merck) advanced mCRPC data in the New England Journal of Medicine from the phase 3 PROfound trial and the announcement regarding achievement of the key secondary endpoint of overall survival. As Dr José Baselga quite rightly noted, this is very good news indeed because:

“Overall survival in metastatic castration-resistant prostate cancer has remained extremely challenging to achieve.”

We’ve rather more trial misses in this disease setting than successes from various therapies over the last few years including ipilimumab, PROSTVAC, alisertib, and atezolizumab, to name a few off the top of my head.

Related to mCRPC, let’s also not forget the upcoming PDUFA date later this month for Clovis’s rucaparib in the very same indication.

Not to be outdone on the PARP front, just a few days GSK received FDA approval for niraparib as first-line monotherapy maintenance therapy for women with platinum-responsive advanced ovarian cancer – regardless of biomarker status – based on the phase 3 PRIMA study presented at ESMO last year and simultaneously published in the NEJM. Recall that the majority of women (51%) had homologous-recombination deficiency (HRD) and this subset saw the greatest benefit.

Flying high in the DDR space?

We have now seen clinical benefit in the PARP inhibitors in four tumour types driven by DNA damage repair (DDR) deficiencies, namely ovarian, breast, pancreatic, and prostate cancers.

How do we go about extending the concept of DDR in terms of the biology of other tumour types?

A number of related pathway targets have been investigated, including ATM/ATR, Chk1, Wee–1 and others, with mixed success.

It’s not the nature of oncology R&D to stand still, however; what if we could turn things on their head and think creatively about the problems still to be addressed?

One particular new company to the PARP space is doing just that… so what are they doing and what’s different about their approach?

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Who’s King of the PARP castle?

After yesterday’s review and expert commentary on the phase 3 PROfound trial presented in the Presidential Session at ESMO 2019, we’re continuing our look at PARP inhibitors in advanced prostate cancer.

Perhaps surprisingly, there were a lot of insights to be found in the posters that were presented and discussed at the meeting for other PARPs in clinical development.

How do these stack up against olaparib? We’re not fans of cross-trial comparisons as they always come with a mandatory health warning, but if you want to consider the emerging landscape, it is important to be aware of the different patient populations, lines of therapy, and details of the trial designs.

For additional perspective at ESMO19, we spoke to a European prostate cancer expert who kindly talked about his clinical practice and also offered insights into a PARP clinical trial he and colleagues presented in Barcelona.

Who will be King of the PARP castle in advanced prostate cancer?

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We’ve heard much about the role of PARP inhibitors in ovarian and breast cancers where there is sensitivity to these agents in women with DNA damage repair defects, but what about advanced prostate cancer?

Following the publication of the phase 2 trial TOPARP in the NEJM in 2015, we’ve been eagerly awaiting the outcome of a series of phase 3 studies with these agents in metastatic prostate cancer in multiple different lines of therapy.

Dr Oliver Sartor at ESMO19

Following on from our daily coverage from ESMO in Barcelona last week where we looked at some of the pros and cons as they appeared during the presentation by Dr Maha Hussain (Chicago) from the PROfound trial, it’s time to share some expert opinions.

The study she presented evaluated the PARP inhibitor, olaparib, versus next generation AR anatgonists abiraterone or enzalutamide in refractory metastatic castrate-resistant prostate cancer (mCRPC).  Interestingly, it soon became rapidly clear that many casual observers missed some important nuances from the myriad of top-line news articles and summaries.

The devil, as always, is in the details.

To further our readers education on this important topic, BSB interviewed a prostate cancer thought leader, Dr Oliver Sartor (right) for his personal perspectives and look at the take homes from the lens of an experienced triallist in this niche.

Let’s see what he had to say about PARP inhibitors in advanced prostate cancer, as well as the PROfound and TRITON studies…

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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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DNA Damage Repair (DDR) has come a long way over the last decade or so from preclinical development through clinical trials, including some notable failures along the way. What began initially with PARP inhibitors, has now expanded into other related targets in the pathway, including ATM/ATR, WEE–1, Chk1/2, DNA-PK, and even Fanconi anemia genes such as FANCA/BC/D1, BRIP1 and PALB2, which are considered an indication of BRCAness where there is also chromosomal instability and homologous recombination.

Top 10 DDR targets and molecules at AACR19

At AACR last week, there was plenty to learn about in the ever-expanding DDR niche in terms of new data from a relatively new target such as DNA-PK to updated clinical data on WEE–1 and Chk1 inhibition to early data on PARP in a new tumour type to add to the growing list of ovarian, breast, and prostate cancers that are impacted by DDR therapies.

Included in this post are 10 key targets or molecules in the DDR niche that are of potential interest to readers – we explain why we included them and why the data matters.

Here we take a look at the highlights that we came across in this mini review, which should be useful preparation ahead of yet more clinical data likely being presented at ASCO and ESMO later this year.

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The annual ASCO-SITC meeting (#ImmunoOnc19) was held in San Francisco this year and has come a long way from the inaugural event we attended in Orlando.

Finding the signals amongst the noise

In the original 2017 event, I vividly recall as stirring presentation from Dr Limo Chen on targeting CD38 in solid tumours, last year we wrote an update on GU cancers including the STING pathway.

What’s in store from San Francisco and how do we go about finding key signals from the noise?

Over the next two posts I’m going to focus on new findings in various approaches that either look interesting and worth watching, or where there are lessons that can be learned for future developments.

This time around, some of the highlights surprised even me…

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2018 is likely to be the year of various immunotherapy combinations as we go beyond monotherapy approaches to see which doublets or triplets will yield improved outcomes. Originally, we had expected to see key data last year, but moving overall survival to a co-primary endpoint with PFS in many studies delayed the readouts by 12 or more months.

SGO 2018 – Who dat?

What’s happening now is that we have started to see some of the early data trickle out and there’s much more to come in the next few months as we head into ASCO and ESMO.

The last two months have seen much attention on lung cancer, but what about a less hyper-mutated tumour types such as ovarian or endometrial cancers? What’s happening in these women’s cancers?

Going beyond monotherapy with PARP inhibitors or checkpoint blockade is important if we truly want to start pushing the survival curves upwards and to the right.

It’s time for a new update on this hypercompetitive niche…

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There’s no secret or surprise with our latest AACR Preview as this week the focus takes a slight turns or detour to the annual meeting of the Society for Gynecology Oncology being held in National Harbor, Maryland.

PARP inhibitors in ovarian cancer have been a hot topic since last autumn when the PARP inhibitor data dropped at ESMO in Copenhagen, and was not without controversy either.

We’ve been following the trials, tribulations and even machinations, of the clinical development of olaparib, rucaparib and niraparib for a while now so what’s in store in the latest round of salvoes?

And importantly, what else can we expect to see in DC at AACR next month?

For a tumour type that hasn’t received much attention over the last decade or two, things are distinctly picking up.  Is it all good though?

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Today we continue the second of a two part interview with a global thought leader who is also a scientist-clinician and well versed in cancer research as well as clinical trials.

Old Town Hall, Munchen

We explore how we can do clinical trials better in order to learn via a more rigorous process what works, what doesn’t, and why. After all, we we don’t know why certain approaches didn’t work or what the mechanisms of resistance are, how can we possibly improve?

Randomness is not necessarily a good thing in clinical research, especially if you don’t know what target you’re actually trying to hit!

If you missed the first part of this latest KOL interview and want to catch up then you can find it here (Link).

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