Biotech Strategy Blog

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

Posts tagged ‘PARP inhibition strategy’

The convergence between targeted therapies and immunotherapies with genomics has already started in many areas of cancer research – we can imagine the intersections more as a Venn diagram than as separate entities these days.

Lobster pots on the shore

While former graveyards of R&D such as metastatic melanoma and lung cancer have seen a dramatic revival in positive trials over the last five years, things have languished somewhat in other areas.

Womens cancers such as high grade serous ovarian cancer (HGSOC) and triple negative breast cancer (TNBC) have seen some new developments with the advent of PARP inhibitors as monotherapy or maintenance, but there is still a ways to go in terms of overcoming resistance and improving outcomes further.

You might be puzzled what on earth lobster pots have to do with cancer research? In short it’s an apt analogy from life because while there is much promise in the right situation (under the sea in a good situation), they can also look like a helpless mess (abandoned on the shore).  Oncology R&D is a bit like that too and finding the right situation viz molecule development and clinical trial design, not to mention discontinuation is very similar in that respect too.

In our latest AACR18 Preview, we take a look at an underappreciated oncology drug class and look at the opportunities for future combinations that may take a few readers by surprise…

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Last October I posted two updates on small cell lung cancer (SCLC). One explored the broad SCLC landscape, while the second was a detailed analysis highlighting the red and green flags to watch out for in the Rova-T TRINITY study.

My sombre conclusion or prediction, if you will, was not particularly well received at that time:

“My sense is that the median PFS and OS in the allcomer ITT population will remain modest and in line with what we might expect from historical chemos in 3L SCLC.”

Dismal happenings are to be expected…

This morning AbbVie announced that they will not be filing for accelerated approval of Rova-T in 3L SCLC based on the interim analysis.  In other words my expectations for this trial were met, although there are many who will be very disappointed at the results.

What matters though is not just how disappointing topline results might be per se, but why they occurred, what we can do about it, and most importantly, where we go next.  There’s a lot more to this than might initially be obvious from the press release.

That’s what this new post is all about… first a post mortem, then the obstacles to be addressed, and finally, what we can look forward to in SCLC…

On a happier note: there may be some surprises ahead!

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It amuses me to realise that I’ve been writing about and following PARP inhibition since 2006 or so, when the field was in that twilight zone of early drug development between preclinical and clinical, thus just beginning to hit some sort of consciousness and broader interest in cancer research.

The AACR Molecular Targets meeting in 2009 was the first scientific meeting I covered as a science writer on the old Pharma Strategy Blog, which focused on early drug development from preclinical to phase 2 – after that I would rapidly lose interest and move on to the next new shiny scientific lure to research and discuss. No doubt this eager new writer ran about like an overenthusiastic little puppy in the poster halls chatting to scientists about their research, much to the amusement of the more staid press room, who at that time probably never ventured out of the darkened basement gloom.

In one of the press briefings there, I met an engaging and thoughtful scientist who was presenting his poster on PARP and synthetic lethality. He kindly took the time to explain in plain English a commonsense analogy that was most helpful for grasping complex concepts. Having sat through several long talks from luminaries in the field such as Drs Hillary Calvert and Alan Ashworth that covered double strand breaks and DNA repair mechanisms, it was a most welcome respite in the hurly burly of the conference!

Imagine his imagery…

You have a four legged coffee table or wooden chair and one of the legs breaks off or is damaged. The table remains standing, albeit less stable than before. Now a second leg breaks, and inevitably, the table is so unstable that it falls over.

Once you grasp that simple analogy for synthetic lethality, you have the basic idea of DNA double strand breaks and how inefficient repair can lead to vulnerabilities in the tumour that can be exploited.

The scientist I spoke to in Boston back in 2009 was Dr Mark O’Connor.

He was involved in DNA damage response research at a little known private company in Cambridge, UK called KuDos, who were subsequently acquired by AstraZeneca. Nearly a decade on and Dr O’Connor is still at the company; he now heads up their DNA damage response area.

Dr Mark O’Connor, AZN

With olaparib (Lynparza) since approved by the FDA in ovarian cancer and slated for the ASCO 2017 plenary session for HER2- breast cancer, things have certainly changed a lot since those early heady days of KuDos and the R&D journey has not been without its notable ups and downs along the way.

In Chicago earlier this month, I had the pleasure of catching up again with Dr O’Connor to learn more about the journey, and importantly, where things are going next.  It’s quite an interesting roller coaster ride, to be sure!

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Often times when we see promising data presented at a cancer conference, we interview a thought leader and post the expert opinion with additional commentary and insights.

ASCO17 OlympiAD Plenary

At ASCO, we decided to take a different approach, a twist on the usual fare… given that two of the phase 3 trials, OLYMPIAD and APHINITY, received significant attention and focus involved breast cancer, we reached out to numerous experts and curated their sentiments on both studies.  For completeness and fair balance, these included industry and academic opinions.

Today, we begin with the OLYMPIAD trial presented by Dr Mark Robson on behalf of his colleagues exploring the role of the PARP inhibitor, olaparib (Lynparza), in HER2-negative metastatic breast cancer with germline BRCA mutations.

There’s a lot to consider here, not least is where do we go next from here and which PARP combination approaches are researchers most excited about?

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The DNA in a human cell undergoes thousands damaging events per day, generated by both external (exogenous) and internal metabolic (endogenous) processes. Unfortunately, some of these changes can generate errors in the transcription of DNA and subsequent translation into proteins necessary for signaling and cellular function. Genomic mutations can also be carried over into future generations of cells, if the mutation is not repaired prior to mitosis.

This DNA damage repair from normal cell cycle activity is a field with a large body of research over the last decade or so. Damage to cellular DNA is ultimately involved in mutagenesis and the development of some cancers.

Clinically, there are a number of different ways that can be utilised to help repair the damaged DNA. One approach that is included in this category is the poly ADP ribose polymerase (PARP) inhibitors, which target the enzyme of the same name. I first wrote about PARPs on PSB way back in 2006 – you can check out the short posts for some basic background information on PARPs (here).  Fast forward to 2014, and another post highlights some of the challenges and issues associated with developing targeted agents, including PARPs.

In 2009, the hot buzzword of the AACR Molecular Targets meeting was ‘synthetic lethality’, a term that is highly relevant to understanding DNA mismatch repair and PARP inhibitors. Hilary Calvert gave a detailed talk on synthetic lethality and PARP inhibition at that meeting, where many attendees, myself included, were struggling to understand quite what he meant.

The lead scientist at KuDos, Dr Mark O’Connor, (note: KuDos was subsequently bought by AstraZeneca) had a nice poster on their PARP inhibitor in development at that very same meeting.  I’ll never forget our animated discusson and his simple analogy of a three-legged coffee table, removing one of the legs to cause instability and falling over as a great metaphor for what happens with synthetic lethality.

To this day, every time the leading British researchers in this field, Profs Hilary Calvert or Alan Ashworth, mention ‘synthetic lethality’, I immediately think of the unstable and wobbly coffee table visual!

Incidentally, the KuDos/AZN PARP compound in preclinical development back in 2009 subsequently became olaparib… is now Lynparza, marketed by AstraZeneca, and available on both the US and EU markets for refractory ovarian cancer with germline BRCA mutations. The EU approval is specifically in platinum-sensitive disease.

The Alamo San Antonio TexasSince then, we’ve seen iniparib (Sanofi) fail badly in phase 3 in a poorly designed catch-all study that didn’t screen or test patients with triple negative breast cancer (TNBC) for BRCA mutations (doh!) and three new promising next generation PARP inhibitors emerge – veliparib (AbbVie), rucaparib (Clovis) and talazoparib / BMN 673 (Biomarin).  All three of these have received attention on this blog in the past (check the links).

In this article, we discuss what’s happening with Biomarin’s PARP program based on their latest update at the recent San Antonio Breast Cancer Symposium (SABCS) last month.

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I will be flying to Stockholm next week for the European Multidisciplinary Cancer Congress (twitter #EMCC2011), more commonly known as ECCO or ESMO 2011.

What are the sessions that look interesting at the meeting? I previously wrote about the phase III ALSYMPCA trial data for Alpharadin that will be presented as a late breaking abstract.

In addition, the best abstract at ECCO 2011 is on vismodegib in basal cell carcinoma.  Sally Church on Pharma Strategy Blog has written extensively about the hedgehog pathway and role of smoothend inhibition in the treatment of cancer.

What else has attracted my attention at ECCO 2011 in Stockholm? In looking at the preliminary program I was struck by the large number of scientific symposia throughout the meeting. However, many occur at the same time! On Saturday 24th two in particular caught my attention:

Molecular Imaging of Hypoxia

Nanotechnologies for Targeted Drug Delivery

Having written about hypoxia and nanotechnology on this blog, I will probably go to one of those two sessions.

Later in the conference, there is another block of scientific symposia on Monday 26th, again all at the same time! Several that look particularly interesting include:

  • How to understand and to Reverse Drug Resistance in Metastatic Breast Cancer
  • From New Targets to New Drugs in Prostate Cancer
  • Tailoring Personalized Medicine for the Future
  • The Role of IGFs/IGF-1R Pathway in Paediatric Malignancies

And in case one still hasn’t had enough science, there’s another group of scientific symposia on the final day of the conference on Tuesday, 27 September including:

  • Unravelling Ras PI3 Kinases Targets 
  • PARP inhibiting strategies: from Molecular Mechanisms to Rational Clinical Applications

I expect Stockholm to be expensive, they jokingly say you can buy a brewery in America for the price of a beer in the city, but it looks like there’ll be some interesting news and scientific data from the meeting. Hopefully I’ll have a few hours sometime to see something of what looks like a stunningly beautiful city.

If you plan to be in Stockholm do let me know. I can be reached via twitter (@3NT).

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