Biotech Strategy Blog

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

Posts from the ‘Ovarian’ category

Copenhagen – PARP inhibitors are creating quite a lot of controversy here at the 2016 ESMO Congress.

Yesterday, we heard the data for rucaparib (Clovis Oncology) as monotherapy treatment for the advanced ovarian cancer patients with BRCA mutations who have been treated with 2 or more chemotherapies.

In a totally different ovarian cancer indication, today at #ESMO16 we heard the results of the phase 3 trial for niraparib, the PARP inhibitor from Tesaro, that many thought was superior to the rucaparib data, ignoring the fact you can’t make comparisons for maintenance versus relapsed/refractory treatment.

The niraparib ENGOT trial was presented in today’s plenary Presidential Symposium by Dr Mansoor Mirza and simultaneously published in The New England Journal of Medicine (link). It was also featured in a media briefing earlier today in Copenhagen.

esmo-2016-press-briefing

In this piece we’ve taken a critical look at the Tesaro (NASDAQ: TSRO) niraparib data and the controversial claim made by their principal investigator, Dr Mirza, that the data shows there is no need for a companion diagnostic to be associated with this drug.

In other words, the intent that regulatory approval will be sought for this drug as maintenance therapy for platinum-sensitive ovarian cancer patients, irrespective of whether they have a BRCA mutation or homologous recombination deficiency (HRD).

This post provides commentary on this and offers the perspective of a leading ovarian cancer expert with deep experience of companion diagnostics in this field.

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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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Prof Fran Balkwill Barts Cancer InstituteWhen it comes to cancer immunotherapy drug development, one of the challenges is that we can’t accurately predict from preclinical mouse models what will happen in people. The result is a rush into the clinic to test in human subjects.

We do need better preclinical models, which is why it was interesting to hear recently on an episode of Health Check (BBC World Service) about a 3D tumour model that is being developed at Barts Cancer Institute.

Professor Fran Balkwill (pictured), who leads the Centre for Cancer and Inflammation, kindly spoke to BSB about the work she and colleagues are doing to model the tumour microenvironment (TME) in high-grade serous ovarian cancer.

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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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One of the (many) highlights for me at the recent annual meeting of the American Association for Cancer Research (AACR) was a “Meet the Expert” session presented by Professor George Coukos.

Prof George Coukos AACR 2016

Prof George Coukos AACR 2016

Professor Coukos is Director of Oncology at the University Hospital of Lausanne and Director of the Ludwig Institute for Cancer Research in Switzerland.

Ovarian cancer is becoming a fascinating battleground for cancer immunotherapy, with multiple challenges that must be overcome before we see improvements in outcomes, especially for women advanced disease.

The interview with Prof Coukos is a follow-on to the one we did on advanced ovarian cancer and checkpoint blockade at ECCO 2015 in Vienna with Dr Nora Disis (Link).

If you missed it, you can still listen to highlights in Episode 7 of the Novel Targets Podcast (Link).

After his AACR presentation, Prof Coukos kindly spoke with BSB and in a wide ranging discussion, highlighted some of the innovative clinical trial strategies he is working on to move the cancer immunotherapy field forward in ovarian cancer.

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Dr Nora Disis ECC 2015

Dr Nora Disis, U Washington

At the recent European Cancer Congress in Vienna, Austria, Dr Nora Disis  (pictured right) kindly spoke with BSB about her clinical research with avelumab (Merck KGaA/Pfizer), a cancer immunotherapy that targets the programmed death-ligand 1 (PD-L1).

Dr Disis (@DrNDisis) who is Editor in Chief of JAMA Oncology (@JAMAOnc) and a Professor of Medicine at the University of Washington, presented a poster at the meeting (Abstract #2749) with updated data for the phase 1b trial of avelumab in relapsed/refractory ovarian cancer.

In addition to reviewing the results with avelumab and in particular, the biomarker results for PD-L1 and CA125 expression, Dr Disis talks about why avelumab is different from other anti PD-L1 checkpoint inhibitors.

This is particularly important when considering a competitive and crowded marketplace where path-to-market strategies become more focused and critical.  Certainly some of the issues discussed in detail present a nice case study of some the challenges facing pharma companies when you are 5th, 6th or more to market.  Differentiation becomes a key driver that needs to be considered and incorporated into the clinical development plan.

She also talked candidly with BSB about some of the challenges and opportunities for checkpoint inhibitors and the PD-L1 in ovarian cancer, a disease where there is a high unmet medical need for effective new therapies.

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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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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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Liverpool: In the United Kingdom, 1 in 48 women will be diagnosed with ovarian cancer, with 90% of cases in those aged 45 or greater.

How long you will live is determined by how early the cancer is diagnosed and treated.

In England, 9 out of 10 women diagnosed with ovarian cancer at the earliest opportunity (Stage I) will live 5 years according to data from the Anglia Cancer Network published on the Cancer Research UK website. This drops to just 2 out of 10 if diagnosed at Stage III.

The challenge is that the majority (60%) of women in England are diagnosed with stage III or IV disease.

The result is that the UK has survival rates below other European countries, in other words women die earlier from the disease than they should. In the North West of England, and in particular in Liverpool, ovarian cancer detection and survival is below the national average.

Possible reasons for this may be that primary care doctors fail to pick up early symptoms of cancer or that women don’t go and see a doctor until too late.

Abdel-Rahman et al in a 2009 paper published in the British Journal of Cancer estimated that almost 2,400 deaths within 5 years of diagnosis could  be avoided if survival  from  ovarian cancer in Britain equalled the best in Europe.

In an effort to improve ovarian cancer outcomes, the UK government public health department and National Health Service have launched a Be Clear on Cancer campaign with radio and TV ads in the North West of England from 10 February to 16 March, 2014.

Be Clear on Cancer Campaign to raise ovarian cancer awareness

Luciana Berger MPLast Saturday (International Women’s Day) I spoke with Liverpool Wavertree MP and Shadow Minister for Public Health Luciana Berger MP (@lucianaberger) who was handing out ovarian cancer awareness leaflets to shoppers at the St John’s Shopping Center in Liverpool.

The main message she gave me is that if women experience prolonged bloating most days for 3 weeks or more, they should see their doctor.

Whether this campaign results in more referrals and earlier diagnosis is something that will be measured. If survival rates can be significantly improved through raising cancer awareness then these campaigns will merit more media attention and funding in future.

This morning in Amsterdam brought some interesting breast and ovarian cancer presentations that I thought deserved a quick recap.

One is potentially practice changing in HER2 breast cancer and the other is a new product in development (Biomarin’s BMN 673) that is worth watching out for:

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