Biotech Strategy Blog

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

Posts tagged ‘Advanced Prostate Cancer’

Who’s King of the PARP castle?

After yesterday’s review and expert commentary on the phase 3 PROfound trial presented in the Presidential Session at ESMO 2019, we’re continuing our look at PARP inhibitors in advanced prostate cancer.

Perhaps surprisingly, there were a lot of insights to be found in the posters that were presented and discussed at the meeting for other PARPs in clinical development.

How do these stack up against olaparib? We’re not fans of cross-trial comparisons as they always come with a mandatory health warning, but if you want to consider the emerging landscape, it is important to be aware of the different patient populations, lines of therapy, and details of the trial designs.

For additional perspective at ESMO19, we spoke to a European prostate cancer expert who kindly talked about his clinical practice and also offered insights into a PARP clinical trial he and colleagues presented in Barcelona.

Who will be King of the PARP castle in advanced prostate cancer?

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San Francisco

San Francisco – Yesterday at the ASCO Genitourinary Symposium, Dr Kim Chi noted that emerging data suggests that ctDNA appears to give better picture of tumour mutations than biopsy and can also monitor tumour load. This is an encouraging development that may facilitate increased use of the diagnostic as a helpful biomarker of response in clinical trials with immune checkpoint blockade.

We also know that prostate cancer sits firmly in the middle of the now famous Alexandrov and colleagues tumour mutation burden (TMB) analysis, but what factors are important in our understanding of the underlying biology of the disease?

There are many inhibitory factors exerted on the tumour microenvironment and thase may vary not only by tumour type e.g. renal cell carcinoma may have a greater influence from VEGF than prostate cancer, but also in individual patients.

With this in mind, I wanted to explore some new combination data being presented at the meeting, as well as look aspirationally to some potential combinations currently in development that may have escaped many people’s attention.

In this post, we take a look at current and future implications that keen observers should be watching out for…

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Wiesbaden, Germany – Last night Bavarian Nordic dropped the unfortunate news that the phase 3 PROSPECT trial exploring the PROSTVAC vaccine in combination with GM-CSF in asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer (CRPC) was futile.

Source: Bavarian Nordic

Once you miss the overall survival (OS) endpoint, that’s it folks – there’s no other choice but to say the therapy failed, harsh though that may sound.

There are, however, a number of important points to consider from here that are worthy of further discussion.

Here, we post an analytical review and look at a number of factors that could have impacted the outcome.  It’s rarely one simple thing because the immune system is highly complex and multi-faceted.

Hopefully there will be important learnings from this study that will advance the IO and prostate cancer fields.

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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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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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Amsterdam – Earlier today, I had the great pleasure at the European Cancer Congress to interview Oliver Sartor, MD, the Piltz Professor of Cancer Research in the medicine and urology departments of Tulane School of Medicine in New Orleans, LA.

A recognized expert in prostate cancer, Dr Sartor was gracious enough to give me an impromptu interview in the poster hall at ECCO 2013 and share his thoughts about the prostate cancer clinical data presented in Amsterdam.

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Subscribers should see a SoundCloud below that they can click on to listen to the interview with Dr Sartor. If you don’t see it, send me an email and I will provide a private URL link that will take you direct to SoundCloud.

[soundcloud url=”http://api.soundcloud.com/tracks/113217676%3Fsecret_token%3Ds-Ka2sf” params=”” width=” 100%” height=”166″ iframe=”true” /]

Takeda’s orteronel (formerly known as TAK-700) may be on its way to “dog drug heaven” after an interim analysis of the ECM-PC 5 phase 3 clinical trial showed that men with advanced prostate cancer taking the drug did not live significantly longer (HR 0.894, p=0.226) than those taking an inactive placebo.  Here’s a link to the Takeda press release.

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AZD3514 is a novel Selective Androgen Receptor Down-Regulating Drug (SARD) that showed early preclinical promise for the treatment of Castration-Resistant Prostate Cancer (CRPC).

However the development of this drug in advanced prostate cancer has been terminated by AstraZeneca according to Dr Aurelius Omlin, a Clinical Research Fellow at The Royal Marsden Hospital who presented clinical data on AZD3514 at the 2013 annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago.

I previously wrote about the promising preclinical data for AZD3514 presented by Sarah Loddick at the 2012 annual meeting of the American Association for Cancer Research (AACR) and sometimes drugs when they transition to the clinic just don’t live up to their promise.

That’s what happened here, and it reminds us that testing of drugs on human volunteers remains a key part of drug development despite the inherent risks. (See my post on the TLS deaths on the AbbVie/Genentech ABT-199 CLL dose finding trial)

AZD3514 ASCO 2013 PresentationThe results from a first-in-human clinical trial with in men with CRPC were presented by Dr Omlin at ASCO 2013 (abstract 4511). In his oral presentation, he first noted that:

“AZD3514 is a first-in-class, non-steroidal small molecule androgen receptor (AR) down-regulator that inhibits nuclear AR translocation and results in proteasomal AR protein degradation.”

The phase 1 clinical trial to assess safety and tolerability explored doses ranging from 100mg once daily (OD) to 1000mg OD in capsule formulation, and from 1000mg OD to 2000mg taken twice daily (BID) in tablet formulation. A pretty comprehensive range, but……

“Tolerability of AZD3514 was problematic,” said Omlin. “80% of patients had Grade 1-2 Nausea (n=39 out of 49) and 49% Grade 1-2 Vomiting (n=24 out of 49).”  Additionally, grade 1-2 thrombocytopenia was seen in 33% of patients.  There was no dose limiting toxicity reported.

What killed it for AZD3514 was the fact that according to Omlin,

“Nausea and vomiting were characteristic from the very first dose level starting about 30-60 minutes after dosing and lasting for several hours thereafter.”

However, the drug did show activity in CRPC patients with several patients showing PSA declines including one patient with prior abiraterone exposure.  Two patients with soft tissue disease had confirmed responses according to Recist 1.1. There was also evidence of clinical activity from changes in the number of circulating tumor cells.

Industry analyst, David Miller (@BiotechStockRsr) commented on Twitter, while watching the presentation, that he thought it hard to see the drug progressing in development, and he turned out to be correct:

Dr Omlin concluded his presentation by stating that, “the development of this compound by AstraZeneca as a selective androgen receptor down-regulator in mCRPC has been terminated.”

Sometimes promising preclinical data just doesn’t hold up when it moves into human clinical trials. Another AstraZeneca drug with preclinical promise has gone to what Sally Church, PhD (@MaverickNY) refers to as “dog drug heaven.”

At the 2012 annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago, Oliver Sartor, Professor of Cancer Research and Medical Director of the Tulane Cancer Center in New Orleans told attendees in the educational session on castration-resistant prostate cancer (CRPC) that he was tired of being asked the question of what is the optimal sequence for new advanced prostate cancer drugs?

ASCO 2012 CRPC Prostate Cancer Education SessionThere is “No data,” Sartor told the ASCO 2012 audience. As a result he recommended the use of less toxic therapies first and that patients be involved in the decision making. Not quite the guidance the audience perhaps hoped for.

Sartor is, however, correct that we don’t yet have the data – the clinical trials have yet to be done that will answer the question of what is the optimal sequencing of prostate cancer drugs?

The approval of abiraterone acetate (Zytiga®) for the treatment of men with advanced prostate cancer, post chemotherapy, and the expected approval of enzalutamide (formerly MDV3100) and radium-223 (Alpharadin) have focused attention on sequencing and combination options.

A poster at ASCO 2012 showed that cross resistance may occur between abiraterone and enzalutamide, suggesting that if resistance to one develops it may lower the efficacy to the other if given subsequently. More data and research is needed to validate this finding and understand how resistance develops.

Reciprocal feedback between the PI3-Kinase and androgen receptor (AR) signaling pathways means that blocking the androgen receptor may stimulate the PI3K pathway and vice versa, leading to the tumor trying to ensure its survival. This is particularly important in prostate cancers that have the PTEN tumor suppressor gene, the result is that the targeting of both PI3K and the AR to avoid crosstalk may be required.

The scientific rationale for combining enzalutamide with a PI3-kinase inhibitor was discussed on Pharma Strategy Blog in Sally Church’s video from the 2011 American Urological Association annual meeting. Clinical trials are being planned to investigate the use of PI3-kinase inhibitors in prostate cancer.

I have written more from ASCO 2012 about the emerging challenges in prostate cancer drug development in a guest post published on Xconomy.  Many thanks to Luke Timmerman, National Biotech Editor, for the opportunity to contribute.

Hopefully, there will be more insights available at ESMO 2012 later this year and at ASCO next year on prostate cancer drug resistance, optimal sequencing and the benefits that combinations therapies may offer.

This is part 2 of my interview with Dr Maha Hussain, Professor of Medical Oncology at the University of Michigan.  You can read part 1 about cabozantinib and pain here.

Cabozantinib-Prostate-Cancer-Bone-Effect

At the 2011 ASCO annual meeting, Dr Hussain presented data from a non-randomized phase 2 trial with cabozantinib that showed dramatic improvements in bone scans before and after treatment.

Bones are living tissues that are constantly being remade, a dynamic process that involves formation of new bone and taking up of old bone, a process known as bone resorption.  Cancer cells can interfere with bone remodeling, resulting in increased new bone formation (osteoblastic response) or excessive bone resorption (osteoclastic response).

Bone scans involve the injection of radioactive tracers such as technetium-99m-MDP. In simple terms, the radioactive material detects bone turnover and areas of high bone metabolism.  These show up as darker “hot spots” where the tracers accumulate.

Bone scans have poor specificity because tumors, fractures and infection all lead to hot spots. Also, not all tumors or lesions are detected by a bone scan.  Bone scans have a sensitivity of around 62-89%.

At the 2011 Society for Translational Oncology Prostate Cancer Symposium, Professor Johann de Bono (The Institute for Cancer Research) noted that bone scans do not accurately reflect the activity of the disease in men with prostate cancer.

This raises the question as to what we should conclude from the bone scans seen with cabozantinib.  I put this question to Professor Hussain.

BSB: What is the significance of the bone scans that we see and what should we interpret from them given that bone scans don’t accurately reflect the disease?

Dr Hussain: I will refer you back to my presentation at ASCO originally and my recent AACR presentation.

I have specifically put a slide (together) to address, is what we are seeing a fluke, a function of a technique issue because you are targeting the osteoblasts?  Consequently if you inhibit osteoblastic function, you are not going to see much changes on the scan, or is there more too it?

Dr-Maha-Hussain-ASCO-2011-Cabozantinib-Presentation

The specific slide actually puts in columns the (percentage of) patients who had a partial or a complete resolution on the bone scan, versus those who had stable or progressive disease, and then matches it with other evidence of an anti-tumor effect as in target lesion regressions, progression free survival at I think the 6 month mark if I recall correctly, as in the pain improvement, narcotic use.

Recognizing that by the way the pain and narcotic use, both of these were post-hoc assessments that were done.  Once we saw the observation, the sponsor went back and began asking all the investigators to record these things.  Clearly, the ALK phosph going down, the bone turnover markers going down.

The short audio clip below expands on Dr Hussain’s viewpoint about cabozantinib and bone. Click here if you can’t see the SoundCloud audio player.

Dr Hussain’s conclusion is interesting from a marketing strategy perspective.  She does not position cabozantinib as a bone targeted drug such as Xgeva or a bone targeted radiopharmaceutical such as Alpharadin.  Instead, her view is that cabozantinib should be developed as a “prostate cancer specific drug that does have the added advantage of significant anti-tumor effect in the bone” ie an anti-cancer tyrosine kinase inhibitor (TKI).

This is at odds with how Exelixis appear to be positioning it.  The corporate presentation at the Cowen Annual Healthcare Conference on March 6, 2012 had a strong focus on bone metastases: “Cabozantinib demonstrates unique ability to resolve bone metastases and decrease bone pain in CRPC,” one slide said.

If Dr Hussain is correct and we should consider cabozantinib as a prostate cancer specific drug, then it will need to compete on endpoints with other drugs that have shown an impact on overall survival.

Cabozantinib will likely not obtain regulatory approval on the basis of the bone scans, whatever they may show.

Without demonstrating a significant effect on overall survival, it’s hard to believe that cabozantinib will be able to compete effectively in what is fast becoming a very competitive prostate cancer market.

The final installment of the Biotech Strategy Blog interview with Dr Hussain will cover her perspective on the mechanism of action of cabozantinb, and where the drug, theoretically, might be expected to have most impact in prostate cancer.

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