Biotech Strategy Blog

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

Posts from the ‘Prostate Cancer’ category

Lemons Villa BorgheseThe discovery of a novel target in castration-resistant prostate cancer (CRPC) and the potential of drugs targeting this to delay or overcome adaptive resistance is the subject of today’s post.

Followers of the prostate cancer field know that one of the challenges with drugs such as enzalutamide and abiraterone is that patients stop responding to them over time and they develop acquired resistance.

So imagine that you could give a drug that is not only an effective anti-cancer agent in patients with acquired resistance, but might then allow those treatments to be effective a second time around.  A recently identified druggable target means this is now a possibility.

Of course, it’s early days yet, and the preclinical work has yet to translate into humans, but it’s not hard to see the commercial implications in the prostate cancer landscape for companies such as $MDVN, $JNJ, $TKAI, Bayer and anybody else who wants to be a player.

Interested? Subscribers can login to read more or you can purchase access below. This post is Day 3 in our Road to AACR 2016 series.

San Francisco Cable CarWe’re continuing our post-meeting coverage of the 2016 Genitourinary Cancers Symposium (ASCO GU) that took place earlier this month in San Francisco.

In this post we’re taking a look at the results of a clinical trial with a non-invasive liquid biopsy which in a cohort of patients with prostate cancer identified increased risk of death on abiraterone and enzalutamide, but not taxane chemotherapy.

What struck me listening to this presentation was the simple elegance of an approach, which the presenter likened to the equivalent of “facial recognition” of prostate cancer cells.

As the ASCO GU discussant noted, this could have an impact on clinical trial design, potentially leading to more rapid prostate cancer drug approvals.

Subscribers can login to read more about a biomarker approach, that if validated in a prospective trial, could help identify the optimal sequencing of prostate cancer drugs for patients.

Alcatraz San FranciscoIn yesterday’s post on novel targets in advanced prostate cancer, we looked at a potential new concept that is emerging and being evaluated in clinical trials.

Today, we continue that approach with a look at another novel – and quite different target – as well as ways of repurposing old drugs to help potentially overcome the drug resistance seen with newer therapies for this disease.

Warning: the concepts discussed here may well take you by surprise, although they are based on rational and logical evidence from recent scientific research.

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Dr Nima Sharifi, Cleveland Clinic

Dr Nima Sharifi, Cleveland Clinic

Dr Nima Sharifi (Cleveland Clinic) gave an intriguing talk at the ASCO Genitourinary symposium recently (#GU16), where he explored new ways of targeting and old target i.e. the androgen receptor with abiraterone.

He noted that 2015 was a landmark year for prostate cancer in terms of genetic characterisation of the disease with a key publication in Cell from several groups including Levi Garraway, Charles Sawyers and Arul Chinnaiyan’s labs via the Stand Up to Cancer research program.

It’s a well written and easy to read paper that I highly recommend reading (see Robinson et al., 2015 in the References below).

In addition, the TCGA work is summarised for those interested in Cell via the TCGA portal for prostate cancer (Link) based on integrated profiling of 333 primary prostate adenocarcinoma samples (the separate Cell paper is also included in the References below). For the geeky scientists here, you can also access and query the raw data they collated at the NCI (Link) and the full TCGA datasets for numerous cancers (most were updated in December 2015) can also be found here (Link).

Overall, the SU2C effort is particularly impressive on several fronts and the massive collaboration effort involved sought to determine the genetic factors at play in mCRPC:

“A multi-institutional integrative clinical sequencing analysis reveals that the majority of affected individuals with metastatic castration-resistant prostate cancer (mCRPC) harbor clinically actionable molecular alterations, highlighting the need for genetic counseling to inform precision medicine in affected individuals with advanced prostate cancer.”

The group identified the following key pathways involved in mCRPC, which may lead to more refined clinical work in the near future to optimise and improve the therapy options available for patients with this disease:

Source: Robinson et al., (2015)

Source: Robinson et al., (2015)

One thing that I really hope to see going forward is more focused and rational clinical trials in advanced prostate cancer, where different subsets such as those identified by the SU2C project are tackled with more logical combinations rather than treating everyone the same.  This is a highly heterogeneous cancer, after all.

For example, we saw in yesterday’s post on DNA repair how trials are already starting or planned – some are allcomer trials (why oh why?!) and some are more specific including only patients with mismatch repair that the PARP inhibitors are supposed to target (a much better approach in our view).

It drives me crazy when, even in 2016, we see companies treating a targeted therapy in an untargeted fashion and expect to see positive results from such a diluted approach!

So what do we have in store today?  At the recent ASCO Genitourinary symposium (#GU16), there were a number of intriguing talks that we will continue to highlight for the rest of this week.

After a look at what’s new in PARP inhibition, we now turn our focus and attention to the androgen receptor (AR) and abiraterone acetate (Zytiga), in particular.  This drug was first approved by the FDA in 2010 for CRPC patients who had received prior chemotherapy (docetaxel) and then subsequently in the pre-chemotherapy setting. Both Zytiga and enzalutamide (Xtandi) compete with each other in both of these settings.  One particular challenge is that the therapies work well as single agents but the effect lessens over time as resistance sets in.

A fresh look at abiraterone and steroidogenesis

In this particular talk, Dr Sharifi focused specifically on the androgen receptor (AR) where we have two drugs now approved – enzalutamide, which binds to the AR directly and abiraterone, which impacts steroidogenesis downstream.

The key question being addressed here was that we know abiraterone targets steroidogenesis, but does a bidirectional effect occur i.e. can steroidogenesis come back and regulate abiraterone? If so, is this also a potential mechanism of resistance and how can we improve the clinical situation for patients?

The majority of this work is also covered in recent publications by Li et al., (2015) and Sharifi (2015) see References.

What happens when we give abiraterone to mice and men?

First off, Sharifi described abiraterone and androgens as ‘kissing cousins’ with a shared metabolism, which I found quite amusing. Essentially, the abiraterone is converted to D4A, a metabolite. This occurs consistently in both species, although the concentrations are more variable in humans.

Is D4A inert and doesn’t do much or is it clinically relevant?

To answer this question, they looked at the essential steps in the androgen pathway in CRPC and looked at the impact on DHT synthesis. In two out of three cases, they found that D4A was a more potent inhibitor than abiraterone, while the other was equivalent.

Does D4A bind to the AR?

Both abiraterone and D4A have a common 3-Keto element in their structure, similarly to testosterone. Does this impact AR binding capacity?

In tests, they found that D4A binds to the AR receptor as least as well as enzalutamide and also blocks PSA expression in the same fashion. These data suggest that D4A is an antagonist, not an agonist.

Is their any evidence that this translates into anti-tumour efficacy?

In CRPC xenograft experiments, the researchers found that D4A has more potent anti-tumour activity than abiraterone or enzalutamide, based on the PFS in mice. This may not translate to clinical benefit in humans, but it should at least be worth exploring based on the findings of these models.

Sharifi also mentioned some unpublished work where they noticed that the D4A A/B rings also look like the testosterone structure. Interestingly, this is the substrate for 5α-reductase… so they asked the critical question: can the D4A metabolites be 5α-reduced and 5Ɓ-reduced? Note 5Ɓ-reductase serves to inactivate steroids via a different function.

The answer to both 5α-Abi and 5Ɓ-Abi was yes, they can be reduced.

In addition, Sharifi highlighted the chemical molecules and conformation – 5α-Abi retains a similar plane and conformation structrure as a steroid (i.e. a lookalike), whereas 5Ɓ-Abi is different and has a 90 degree bend at one end, which leads to steroid inactivation.

What happens when you expose prostate cancer cell lines (LNCaPr) to D4A?

They found that within 2 days, D4A was almost depleted because it was converted to the 5α-Abi metabolite.

What are the effects of 5α-Abi on enzymes required for DHT synthesis?

Essentially, they found that 5α-Abi < D4A, i.e. a weaker inhibitor.

What about downstream of metabolism?

Recall that 5α-Abi has the same A/B rings as DHT. They also found that 5α-Abi binds to AR, so does it cause agonist or antagonist effects? It turned out to be an agonist, which would explain the weaker inhibitory effects described above. In mouse xenograft models, this was alos confirmed by a much shorter PFS, which you would expect with an agonist.

What about the good and the bad effects?

By now, we can see that D4A can reduced to both good (5α-Abi) and bad (5Ɓ-Abi) metabolites. This leads to the next question: can we block the bad effects and enhance the good effects? Part of the answer to this lies in data from a phase 2 clinical trial that Dr Mary Ellen Taplin (DFCI) is running in mCRPC (Link).

Here, they are comparing the impact of adding a 5α-reductase inhibitor, dutasteride, to abiraterone plus prednisone versus abi plus steroid alone.

Remember that 5α-reductase inhibitors such as dutasteride and finasteride are old drugs originally approved by the FDA in the early 2000’s for symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate, so prostate cancer experts are well versed with these agents. The standard dose for dutasteride for BPH is 0.5mg/day, although this trial used a much higher dose, 3.5mg/day as an anti-cancer therapy.

The schematic for the trial is as follows – note that by exploring the doublet first then adding in the dutasteride, each patient acts as their own control, which may reduce intra-patient variability:

Phase 2 trial schematic

Phase 2 trial schematic

What did they find?

1) The Good: D4A concentrations nearly doubled when you add dutasteride
2) The Bad: 5α-Abi had a profound (90%) drop when dutasteride was added*
3) The Ugly: 5Ɓ-Abi had no real change in any of the 3 metabolites

*They saw a similar and highly consistent depletion with the other two 5α-Abi metabolites as well.

This preliminary research suggests that when a 5α-reductase inhibitor is added to abiraterone plus prednisone, it blocks the bad effects and enhances the good effects, exactly as we might expect or hope to see.

This is a very nice proof of principle in a small study that such a combination might be useful in mCRPC. What we do need to see now are outcomes data in a larger randomised controlled trial before attempting a more definitive conclusion.

Here are Dr Sharifi conclusions from their work, which I don’t disagree with:

Source: Dr Sharifi at ASCO GU 2016

Source: Dr Sharifi at ASCO GU 2016

Conclusions and Additional Commentary:

“Prostate cancer resistance to castration occurs because tumours acquire the metabolic capability of converting precursor steroids to 5α-dihydrotestosterone (DHT), promoting signalling by the androgen receptor and the development of castration-resistant prostate cancer.”

What this work suggests is that in the short term, there may be some clinical utility in combining a 5α-reductase inhibitor such as dutasteride with a CYP17A1 inhibitor such as abiraterone plus a steroid (prednisone), in order to reduce resistance to therapy and prolong outcomes for men with advanced prostate cancer.

In addition, the authors suggest a novel approach to next generation development of new AR agents targeting steroidogenesis:

“We propose that direct treatment with D4A would be more clinically effective than abiraterone treatment.”

If the clinical results from Dr Taplin’s triplet vs. doublet combination trial are encouraging then don’t be surprised to see a company with a prostate cancer franchise doing a deal with a small company developing anti-D4A inhibitors in the near future since the affinity of D4A for androgen receptors was significantly greater than that of abiraterone, similar to that of enzalutamide, and greater than that of bicalutamide.

As far as I know, the phase 2 study analysis was due to complete in December 2015, so an abstract may have been submitted to ASCO for the 2016 annual meeting (the deadline is this month).  That’s probably the next likely milestone for a comprehensive readout and presentation of the full data.


ResearchBlogging.orgRobinson, D., Van Allen, E., Wu, Y., Schultz, N., Lonigro, R., Mosquera, J., Montgomery, B., Taplin, M., Pritchard, C., Attard, G., Beltran, H., Abida, W., Bradley, R., Vinson, J., Cao, X., Vats, P., Kunju, L., Hussain, M., Feng, F., Tomlins, S., Cooney, K., Smith, D., Brennan, C., Siddiqui, J., Mehra, R., Chen, Y., Rathkopf, D., Morris, M., Solomon, S., Durack, J., Reuter, V., Gopalan, A., Gao, J., Loda, M., Lis, R., Bowden, M., Balk, S., Gaviola, G., Sougnez, C., Gupta, M., Yu, E., Mostaghel, E., Cheng, H., Mulcahy, H., True, L., Plymate, S., Dvinge, H., Ferraldeschi, R., Flohr, P., Miranda, S., Zafeiriou, Z., Tunariu, N., Mateo, J., Perez-Lopez, R., Demichelis, F., Robinson, B., Sboner, A., Schiffman, M., Nanus, D., Tagawa, S., Sigaras, A., Eng, K., Elemento, O., Sboner, A., Heath, E., Scher, H., Pienta, K., Kantoff, P., de Bono, J., Rubin, M., Nelson, P., Garraway, L., Sawyers, C., & Chinnaiyan, A. (2015). Integrative Clinical Genomics of Advanced Prostate Cancer Cell, 162 (2) DOI: 10.1016/j.cell.2015.06.053

Cancer Genome Atlas Research Network. Electronic address:, & Cancer Genome Atlas Research Network (2015). The Molecular Taxonomy of Primary Prostate Cancer. Cell, 163 (4), 1011–25 PMID: 26544944

Li Z, Bishop AC, Alyamani M, Garcia JA, Dreicer R, Bunch D, Liu J, Upadhyay SK, Auchus RJ, & Sharifi N (2015). Conversion of abiraterone to D4A drives anti-tumour activity in prostate cancer. Nature, 523 (7560), 347–51 PMID: 26030522

Sharifi N (2015). Prostate cancer: CYP17A1 inhibitor failure-lessons for future drug development. Nature reviews. Urology, 12 (5), 245–6 PMID: 25823374

Sharifi N (2015). Steroid sidestep: evading androgen ablation by abiraterone. Clinical cancer research : an official journal of the American Association for Cancer Research, 21 (6), 1240–2 PMID: 25432158

Coit Tower San FranciscoAt the recent ASCO 2016 Genitourinary Cancers Symposium (ASCO GU) that took place in San Francisco the week before the JP Morgan Healthcare Conference (JPM), one of the noteworthy presentations was on a novel target for men with advanced prostate cancer.

While JPM may have been a “dud” for many, several companies did take the opportunity to update and discuss their corporate strategy going into 2016, which gave a surprising amount to comment on in our 3 blog posts from the meeting: JPM Day 1, JPM Day 2, JPM Day 3.

In this post we look at the “take homes” from the ASCO GU presentation, and what looks like it could be a new race to market.

It’s good to see novel targets for men with advanced prostate cancer, and potential new treatment options on the horizon!

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Immune checkpoint inhibitors that target CTLA4, PD1 and PDL1 can generate prolonged responses in a minority of patients, but the results so far in prostate cancer have been disappointing. Prostate cancer doctors have not been part of the excitement spreading through the cancer community like a “Mexican wave.”

Prostate cancer has not featured significantly in the cancer immunotherapy news recently, but that’s not to say there is not a lot going on. The phase 3 trial results of ipilimumab (a checkpoint inhibitor of CTLA-4) in the pre-chemotherapy setting of advanced prostate cancer (NCT01057810) are expected soon and there is also the eagerly awaited phase 3 trial of the PROSTVAC vaccine (NCT01322490).

Dr James Gulley ASCO 2015

At ASCO 2015, BSB interviewed Dr James L. Gulley, MD, PhD Chief of the Genitourinary Malignancies Branch and Director of the Medical Oncology Service at the National Cancer Institute (pictured above).

He talked about some of the cancer vaccine work he has done as part of the CRADA (Cooperative Research and Development Agreement) between the NCI and Bavarian Nordic, as well as strategies to help immunotherapy work in those tumors such as prostate cancer that are non-inflamed, where there may be an insufficient immune response for checkpoint inhibitors to work effectively.

Readers may recall we interviewed him at ASCO GU earlier year, “How to make non-immunogenic cancer sensitive to checkpoint inhibitors.” His outstanding work could shape the future of prostate cancer immunotherapy.

This post also includes additional ASCO 2015 commentary on from Dr Oliver Sartor, Professor of Cancer Research at Tulane University, who shared his perspective on the ipilimumab and PROSTVAC phase 3 prostate cancer trials that are due to readout soon.

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Medivation-LogoNew Orleans – in today’s plenary session at the 2015 annual meeting of the American Urological Association (Twitter: #AUA15), Dr Celestia Higano (Seattle), presented the results of the STRIVE trial (NCT01664923) – a multicenter phase 2 study of enzalutamide (Xtandi) versus bicalutamide in men with nonmetastatic (M0) or metastatic castration-resistant prostate cancer (M1). These were men who were asymptomatic or mildly symptomatic.

Dr Celestia Higano STRIVE AUA 2015

Dr Higano noted that this was a very late breaking abstract; topline results were only announced a little over a month ago on April 2.

The TERRAIN trial also compared the efficacy of enzalutamide head-to-head against bicalutamide. We’ve updated our EAU 2015 TERRAIN post with the additional data presented here at AUA 2015 in New Orleans.

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PREVAIL trial EAU 2015We’ve been following the updates on the PREVAIL study evaluating enzalutamide (Xtandi) versus placebo in metastatic castrate-resistant prostate cancer (CRPC) in the pre-chemotherapy setting for a while now. It’s interesting to see how the data evolves over time as it becomes more mature.

The first presentation, back in January 2014 at ASCO GU by Dr Tom Beer (OHSU) reported on the first 540 deaths and was subsequently followed by an update of the survival data at AUA in May of the same year by Dr Chris Evans (UCLA).

This morning at the European Urology Association (EAU) in Madrid in the late breaking session on prostate cancer, the honour fell to Professor Bertrand Tombal (Leuven), who did a very nice job of reviewing the mature PREVAIL data (based on 765 deaths) and providing some context for how the CRPC landscape is being impacted by AR pathway inhibitors.

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EAU 2015 LogoMadrid, Spain – the results of the Medivation/Astellas TERRAIN clinical trial of enzalutamide (Xtandi) versus bicalutamide (Casodex) in men with metastatic castration resistant prostate cancer (mCRPC) were presented today at the European Association of Urology Congress in Madrid (Twitter #EAU15).

Professor Dr. med. Axel Heidenreich. Credit: Universitätsklinikum Aachen

Credit: Universitätsklinikum Aachen

The clinical trial data were presented in a plenary session at EAU15 by Axel Heidenreich (pictured left) who is Professor of Urology & Uro-oncology at the RWTH University and Head of Department & Director of the Urology Program at the University Hospital in Aachen, Germany.

How good are the results, and what impact will they have on the prostate cancer treatment landscape in Europe? Prof Heidenreich kindly spoke with Biotech Strategy Blog (BSB) and shared his thoughts.

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Update May 17, 2015: This post has been updated with the additional TERRAIN trial data presented by Professor Arnauld Villers (Lille) at the 2015 annual meeting of the American Urological Association (AUA) in New Orleans.

Prof Arnauld Villers presents TERRAIN trial data at AUA 2015

Prof Arnauld Villers presents TERRAIN trial data at AUA 2015

We have been following the results of the checkpoint inhibitors for several years now, first with ipilimumab (Yervoy) and lately with anti-PD1 and PD-L1 inhibitors such as nivolumab, pembrolizumab and MPDL3280A. Irrespective of the antibody used, the best results we’ve seen have in melanoma, lung and bladder, but some tumour types such as colon and prostate cancers have barely been responsive at all.

Why is that?

Can we find ways to make non-responsive solid tumours responsive to immune therapies, and if so, what strategies could we employ to enable improved responses and outcomes?

At the ASCO Genitourinary (GU) meeting in Orlando this weekend there were some interesting hints of what might be possible in the not too distant future.

To learn more about this phenomenon, we conducted an interview with a leading cancer immunologist to find out what they are doing to make a difference in the GU space.

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It’s now time to turn our attention to genitourinary oncology and, in particular, prostate, renal and urothelial bladder cancers. This week brings this ASCO GU meeting (#GU15), which is being held in Orlando this year and began this morning.

There are quite a few interesting topics being covered here, particularly in the poster sessions over the next three days. Hopefully, 2015 will also bring more good news in this space as 2014 was a rather dismal one on several fronts!

We decided to highlight some of the most interesting abstracts on castrate resistant prostate cancer and urothelial bladder cancer in our latest conference preview.

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