Biotech Strategy Blog

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

Posts tagged ‘enzalutamide’

After the intensity of gastrointestinal cancer, we now turn our attention to genitourinary (GU) cancers with the upcoming ASCO GU meeting later this week in Orlando.

Two of the big topics here will be prostate and renal cell (RCC) cancers.

Unfortunately, the long awaited data in adjuvant RCC demonstrated that early treatment with sorafenib or sunitinib did not improve outcomes in locally advanced kidney cancer after resection. According to the ASCO press release, the trial conducted by Dr Haas and colleagues at U Penn discovered that:

“The average period to disease recurrence was similar between those who received sorafenib or sunitinib after surgery (5.6 years) and those treated with placebo (5.7 years).”

We will therefore turn our attention to castration resistant prostate cancer (CRPC).

One of the recent and ongoing controversies is splice variants, especially AR-V7, which is thought by some research groups to confer resistance to the hormonal therapies, enzalutamide and abiraterone. The big question though, is does it, and how useful is an assay in helping to determine appropriate therapy? Are there other factors at play?

We looked at the latest data and put the findings in context with what we know from other published research.

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Medivation-LogoThere’s nothing better than seeing good news in the early morning email alerts I have set up on cancer research!

 

astellas-logo-no-sloganToday, it was the turn of Astellas and Medivation to announce the results of the TERRAIN study, which is a primarily European phase 2 trial that began in March 2011 in the prechemotherapy setting for castrate resistant prostate cancer (CRPC). The trial met its primary endpoint of progression free survival (PFS).

 

Why is this an important landmark in CRPC and what does the initial data show?

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A lot has happened this month with San Antonio Breast Cancer Symposium (SABCS) and other data emerging that it could be subtitled:

A brief tale of two breast cancer drugs

SABCS San Antonio CrowdAt SABCS a couple of things looked pretty intriguing indeed. One we will cover in the New Year, along with an in-depth expert interview on the topic, while the other is the main focus of today’s note.

In the last post of 2014, it’s time to address some pertinent questions on triple negative breast cancer (TNBC) from subscribers – there is good news to report here, unlike the surprising MARIANNE results for Kadcyla and Perjeta in frontline HER2+ disease that were announced early this morning.

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A big thank you to all who have supported Biotech Strategy Blog Conference Coverage this past year. Wishing you good health, happiness and prosperity in 2015. See you on the other side!

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This last week saw the ASCO Breast Cancer Symposium in San Francisco, although very little caught my attention from a drug development point of view. Much of the attention seemed to be focused on surgery, genetic counselling and screening.

With the 2014 European Society of Medical Oncology (ESMO) conference in Madrid coming up fast in only 2 weeks time, it seems a good point to take a look at what’s on the slate there, since there are some important clinical trials being presented there with new data that we can expect to hear a lot more about.

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Companies mentioned: Roche/Genentech, GSK, Novartis, AstraZeneca, Medivation, Astellas
Drugs mentioned: Pertuzumab, trastuzumab, lapatinib, PI3K inhibitors, olaparib, enzalutamide

There are a couple of important breast cancer trials with data being presented for the first time at Madrid.

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At the ASCO GU meeting in January, Dr Thomas Beer presented the initial data for the PREVAIL trial, which explored enzalutamide (Xtandi) in castrate resistant prostate cancer (CRPC) prior to chemotherapy. Reactions to the data were mixed with many analysts, perhaps naively, focusing on the significant temporal survival benefit (2 months) rather than the 29% hazard ratio, which demonstrates the magnitude in the reduction in the risk of death over the control arm.

This weekend at the American Urological Association (AUA) meeting in Orlando, Dr Christopher Evans (UC Davis), presented the updated data, including the survival curves and a subset analysis for visceral and non-visceral disease. He focused on the clinical benefits that were clinically meaningful to the urology audience.

I have to say that the data shown was both compelling and impressive to me.

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Over the last few years we have seen new therapies emerge for the treatment of advanced prostate cancer from immunotherapy to chemotherapy and second generation hormone therapies. Each of these has increased survival and outcomes. Along the way though, a host of other agents have fallen by the wayside with a raft of negative phase III trials that did not live up to their phase II promise. These include atrensentan, dasatinib, ipilimumab, lenalidomide and more recently, custirsen.

Much of the focus has, however, been on the hormonal drugs, abiraterone (Zytiga) and enzalutamide (Xtandi) in both the pre and post chemotherapy settings. One thing has become clear though – over time the responses attentuate as resistance sets in. This is very common with oral therapies.

Some big questions to consider here are:

  • What causes it?
  • How can we overcome adaptive resistance?
  • Would combination approaches produce synergistic results?
  • Or should we consider new targets with a different mechanism of action (MOA)?

The answers to these questions are now being eagerly explored through basic, translational and clinical research. I was very impressed with the quality of research and breadth of fresh ideas and approaches emerging from the SBUR, SUO and UOR sessions at AUA this year, including new combination trials already in the planning phase.

In the past, Bertrand Tombal (Belgium) talked about the Grand Cru year for clinical research in CRPC. In the future we may well look back at 2014 as a similar Grand Cru year for basic research for prostate cancer, if the findings translate to clinic. The bench-to-bedside process is very much alive and well in urologic research.

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We hope that everyone had a relaxing holiday break and now it’s time to get back to work.  Tomorrow I will review some more of my thoughts in the immuno-oncology space, since that area had a tremendous amount of progress in San Diego with lots of new ideas to process and summarise.

In the meantime, a few people have written in and asked about what was happening with overcoming resistance in various tumour types, was there anything new to say in that space that was in addition to the the detailed previews we covered before the conference?

Actually, there was a quite a few posters and presentations that caught my eye, so I thought this would be a good idea to review them here:

Lung Cancer: HER2, VEGF, T790M, EGFR, erlotinib, gefitinib, trastuzumab, bevacizumab, CO-1686, AZD9291

Prostate Cancer: mTOR, PI3K, Androgen Receptor, enzalutamide, abiraterone, CC214–2, ARN–509, BET Bromodomian inhibition, ODM–201, GDC–0980, GDC-0068, PF–04691502, BKM120, BEZ235

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Since 2004, six new prostate cancer treatments have been approved for advanced prostate cancer: docetaxel (Taxotere), sipuleucel-T (Provenge), cabazitaxel (Jevtana), abiraterone (Zytiga), enzalutamide (Xtandi), radium-223 (Xofigo).

In the process, the competitive landscape has been radically transformed.

What we have seen more recently with the PREVAIL and COU-AA-302 data is a move to treat mildly symptomatic men earlier in metastatic disease prior to chemotherapy, thereby delaying disease progression, and in the case of enzalutamide, improving overall survival.

But how early can you go?

The focus of several companies looking to bring new prostate cancer drugs to market is now shifting from symptomatic metastatic castrate resistant prostate cancer (mCRPC) to earlier in the disease setting, i.e. asymptomatic M0 disease.

There are number of critical questions that need addressing, including:

  • Should we treat men with metastatic (M0) castration-resistant prostate cancer (CRPC) who are asymptomatic?
  • Will the treatments be able to demonstrate that taking them means men will live longer and feel better?
  • Will there be a market for AR antagonists such as enzalutamide, ODM-201, and ARN-509 in M0 prostate cancer, where large randomised phase 3 trials are either underway or are planned?
Prof Tombal at ASCO GU 2013

Prof Tombal at ASCO GU 2013

During ASCO GU, I asked one of the leading thought leaders and researchers into this area for his candid perspective.

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This week we turn our focus to the American Society of Clinical Oncology Genitourinary (ASCO GU) symposium being held in San Francisco.

The hottest topic is highly likely to be the Medivation and Astellas data for enzalutamide (Xtandi) in the pre-chemotherapy setting in men with advanced prostate cancer who are asymptomatic or slightly symptomatic and naive to chemotherapy.  Previously, I wrote in detail about the Medivation announcement regarding the interim analysis where the PREVAIL trial was found to meet its primary endpoint (open access).

Dr Tom Beer, OHSU

Dr Tom Beer, OHSU

The company subsequently stated that the data had been accepted as a late breaker for the the ASCO Genitourinary meeting in San Francisco this weekend.  That data is being presented on Thursday morning in the oral prostate cancer session by Dr Tomasz Beer (OHSU), who is the Deputy Director of the Knight Cancer Institute and a prostate cancer specialist.

The ASCO GU 2014 abstracts will be available for perusing as of 5pm ET today.

This week I caught up with Dr Beer to discuss not only the details relating to the PREVAIL data, but also how enzalutamide (Xtandi) potentially fits in the advanced prostate cancer competitive landscape given that he also participated in the abiraterone (Zytiga) COU-AA-302 trial in the same clinical setting.

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