Biotech Strategy Blog

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

Posts tagged ‘rucaparib’

westminster-embankmentToday’s news that an FDA Oncologic Drugs Advisory Committee (ODAC) review will not be required for rucaparib is good news for Clovis Oncology. The company announced this via an SEC 8K filing:

“The Food and Drug Administration (“FDA”) has notified Clovis Oncology, Inc. that FDA is not currently planning to hold an advisory committee meeting to discuss the Company’s New Drug Application for rucaparib.”

However, given the unmet medical need in ovarian cancer, a lot of companies are targeting both platinum sensitive and platinum resistant disease.

In our fourth preview of the forthcoming European Society for Medical Oncology (#ESMO16) meeting we’re looking at 9 key ovarian cancer abstracts to watch out for at ESMO.

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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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Beyond the late breaking abstracts and plenary sessions at the European Cancer Conference being held in Vienna, Austria later this month, what other important topics can we expect to hear about?

ECCO 2015 Vienna

We covered the former in the last article on Biotech Strategy Blog, today we turn our attention to the proffered (oral) sessions and what we can learn from those sessions and the expected data that is due to be presented.

There are a number of interesting topics and new data slated for presentation that are worthy of review and highlighting in a What To Watch out For (W2W4) format.

Here’s our take on the potential highlights at the meeting.

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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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Ovarian cancer is an often neglected area in cancer drug development and historically has often been one of the last solid tumours to be evaluated as part of a life cycle management program. There are a number of reasons for this, but recently that situation has begun to change as our knowledge of the underlying biology improves and new agents are developed that target the particular oncogenic aberrations.

It is a tumour type that ranks 5th in cancer deaths amongst women and accounts for more deaths than any other gynaecologic cancer. Indeed, in 2014 nearly 22,000 women are estimated to be diagnosed with this cancer in the U.S. and approx. 14,000 will likely die from the disease.

Earlier this month the FDA approved bevacizumab (Avastin) in combination with chemotherapy (paclitaxel plus pegylated liposomal doxorubicin or topetecan) for the treatment of platinum-resistant, recurrent epithelial ovarian cancer (EOC), fallopian tube, or primary peritoneal cancer who have received no more than two prior therapies. The approval was based on the phase 3 AURELIA trial (n=361), which demonstrated an improvement in median progression free survival (PFS) of 6.8 vs. 3.4 months (HR 0.38, P<0.0001). This means that the women in the trial saw a 62% reduction in the risk of their symptoms worsening compared to chemotherapy alone.

Surprisingly, this advance represented the first new treatment option in this setting for 15 years!

The good news is that beyond Avastin, there are a number of other promising agents in development for ovarian cancer. At this year’s EORTC-AACR-NCI Molecular Targets meeting held in Barcelona, new data was presented on several such compounds that are well worth highlighting.

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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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