Biotech Strategy Blog

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

Posts tagged ‘veliparib’

Tesaro’s niraparib is a highly selective poly(ADP-ribose) polymerase (PARP) 1/2 inhibitor that can induce synthetic lethality in tumor cells with homologous recombination DNA repair deficiencies (HRD), including germline BRCA-mutated tumours.  It received a lot of attention yesterday following the company’s announcement that the phase 3 trial successfully met its primary endpoint.  The trial was expected to readout this month, so it was bang on schedule.

ASCO 2016 Posters 5

Braving the scrum in the ASCO 2016 poster hall

The results generated a lot of discussion and also a bunch (half a dozen!) of questions from readers, since there was a lot noise around the top-line data in the press release, but very little real analysis or context.

I was planning on rolling out the draft posts we have been working on Gems from the Poster Halls, which included one focused on ovarian cancer.  It therefore makes sense to combine the poster analysis with a reader Q&A on ovarian cancer, including a detailed look at Tesaro’s niraparib as there are some important subtleties that many have missed.

Inevitably this ended up as a rather meaty analysis rather than the quick review I originally intended!

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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 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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Yesterday, the European Society of Medical Oncology (ESMO) released the abstracts to the poster and poster discussion sessions.  This preview will be quite long by nature of it being the first time we get a look at the topline details behind some of the key sessions and their abstracts for both immunotherapies (especially checkpoint inhibitors) and targeted therapies.  This includes posters and their discussion sessions, plus poster late breaking poster titles.

For reference, you can find the ESMO 2014 poster and poster discussion abstracts can be found here.

In addition, there appears to be some pretty cool presentations in the Special Symposia, which are rather like ASCO scientific symposia and contain a lot of useful information and often strategic ideas about where thought leaders see hot topics going in the future.  This can be very helpful in learning about possibilities for new clinical trials ahead of time. As we focus on the poster highlights today, do check back tomorrow for a detailed look at the scientific symposia.

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PARP inhibitors have had a chequered history as anti-cancer agents from the lows of the failed iniparib (Sanofi) phase 3 trial in triple negative breast cancer (TNBC) and olaparib (AstraZeneca) in ovarian cancer to the highs of the initial waterfall plots for BMN673 (Biomarin) in BRCA-positive breast and ovarian cancers and a successful graduation from the ISPY2 trial in the triple negative signature for veliparib (AbbVie). In between those two extremes, there has been a lot of uncertainty.

ASCO 2014 Poster HallAt ASCO this year, there was a decent crop of new combination data in both posters and oral sessions looking at various PARP inhibitors in breast or high grade serous ovarian cancer with either chemotherapy (typically platinum-based) or targeted therapies such as PI3K (BKM120) or VEGF (cediranib).

Another new development, which was hinted at from previous AACR conference notes was the potential to explore Biomarin’s BMN673 in lung cancer, specifically metastatic small-cell lung cancer (SCLC) and germline BRCA-mutation carrier cancer patients in a poster for a phase 1 dose finding trial.

Wainberg et al., concluded that:

“BMN 673 has antitumor activity in patients with advanced previously treated SCLC and significant activity in patients with gBRCA mut ovarian and breast cancer.”

Emphasis the authors.

For today’s article, we’re taking a slightly different approach. Rather than analyse the clinical data, I wanted to explore physician sentiments around PARP inhibitors and they thought about this class of drug. Is there still traction here or has the rise of immuno-oncology wiped out interest in targeted agents?

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This morning Dr Hope Rugo, Professor of medicine and director of breast oncology and clinical trials education at UCSF, presented the first ever efficacy results from the I-SPY 2 trial in neoadjuvant breast cancer during the San Antonio Breast Cancer Symposium (SABCS) press briefing.

The complex adaptive phase 2 trial design was developed by Dr Laura Esserman, Professor of surgery and radiology at UCSF and Dr Don Berry, Professor of biostatistics at MD Anderson Cancer Center. Dr Berry was no doubt very familiar and experienced with this concept from the adaptive BATTLE trials in lung cancer that MD Anderson have previously completed.

The data discussed here is from one arm from the study, which currently evaluates different investigational regimens in 7 different arms.

The overall goal of the I-SPY 2 experiment was to screen a series of novel agents in combination with standard chemotherapy in the neoadjuvant setting. Patients were randomized to receive a novel regimen given in combination with standard chemotherapy, or standard chemotherapy alone.

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Whew, having just finished the American Society of Hematology (ASH) meeting, we run on to the breast cancer symposium in San Antonio (SABCS), making for a very busy week of data deluge!  Our Post ASH analysis will also run concurrently for a few days.

There are also a number of interesting areas to look out for in terms of interesting breast cancer developments.

Premium subscribers can find out more about the following below:

Companies: Roche, GSK, AbbVie, AstraZeneca, Novartis, Lilly

Drugs: Herceptin, Avastin, Perjeta, Tykerb, veliparib, olaparib, BKM120, ramucirumab, PD-1, PD-L1

Here’s a quick preview of some of the landmark data emerging from this conference, some positive, some negative.

Following on from yesterday’s post about learnings from the Boston AACR-NCI-EORTC conference in immuno-oncology, today’s post focuses on learnings from non-immune R&D, namely monoclonal antibodies and TKIs.

We know that cancer is a very complex topic and that adaptive resistance is increasingly a huge focus, but where are the new developments in this area and what can we learn from them in order to improve outcomes?

Another key area to consider is therapeutic index, that is are we shutting down enough of an oncogenic target’s activity in order to ensure efficacy? We’ve seen this in the anti-angiogenesis field, for example, where many VEGF inhibitors failed before bevacizumab (Avastin) finally cracked the nut in colorectal cancer and shifted the needle in terms of improving overall survival. We are now seeing this happen in other areas too, which will be covered below.

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