It’s the dog days of summer and yet there’s a lot happening on the DDR front from multiple angles.
After a short break from science, this makes now a really good time to reflect and take stock in order to explore some of the key issues facing the field, especially in terms of future combination approaches.
Research that’s appearing now may influence future trial designs – always a nagging worry in Pharmaland that the standard of care can change before you even get your own phase 3 readout! No one likes to be pipped to the post, after all.
With the early WEE–1 news this week and a raft of new PARP readouts, there is much to discuss and also plenty of nuance and subtlety to consider carefully because what looks obvious at first blush may not actually be the case based on prior evidence that many will have forgotten about.
So grab a cup of iced coffee and shades and settle down under your sunbrellas for a pleasant and easy to read review of the various trials, settings, combinations and DDR pathway considerations…
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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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We now turn our sights to targeted therapies and DNA Damage Repair (DDR). This is an important topic that has seen much focus in ovarian cancer of late and will likely see renewed interest in breast cancer at the forthcoming ASCO meeting next month. As we segue from one set of conference coverage to the next, there is inevitably going to be overlap, which is a good thing here as it helps with background and preparation in getting up to speed.
There is no doubt that DDR has had a bit of chequered history over the last decade, whether it be the spectacular (and sadly predictable) flop of Sanofi’s iniparib in triple negative breast cancer (TNBC), the negative ODAC incurred by AstraZeneca’s olaparib in ovarian cancer, or AbbVie’s more recent veliparib failures, to the much more positive events such as three PARP drugs now approved in different lines of therapy in ovarian cancer (olaparib, rucaparib and niraparib).
If ever there was a niche for the roller coaster ride that is oncology R&D, it has to be PARP inhibitors. There’s much more to DDR than just PARP though.
Indeed, there are multiple intriguing targets to explore and also the potential for combinations with cancer immunotherapy approaches that may yield encouraging results in the future.
Can we go beyond ovarian cancer into other tumour types and if so, which ones look encouraging and how woluld we go about exploring those idesa? What makes one approach more successful than another?
Here we explore the world of DDR through the lens one company’s approach and look at what they’ve done, where are they now and where they hope to be. It certainly makes for an intriguing and candid fireside chat.
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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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