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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We’ve heard much about the role of PARP inhibitors in ovarian and breast cancers where there is sensitivity to these agents in women with DNA damage repair defects, but what about advanced prostate cancer?
Following the publication of the phase 2 trial TOPARP in the NEJM in 2015, we’ve been eagerly awaiting the outcome of a series of phase 3 studies with these agents in metastatic prostate cancer in multiple different lines of therapy.
Dr Oliver Sartor at ESMO19
Following on from our daily coverage from ESMO in Barcelona last week where we looked at some of the pros and cons as they appeared during the presentation by Dr Maha Hussain (Chicago) from the PROfound trial, it’s time to share some expert opinions.
The study she presented evaluated the PARP inhibitor, olaparib, versus next generation AR anatgonists abiraterone or enzalutamide in refractory metastatic castrate-resistant prostate cancer (mCRPC). Interestingly, it soon became rapidly clear that many casual observers missed some important nuances from the myriad of top-line news articles and summaries.
The devil, as always, is in the details.
To further our readers education on this important topic, BSB interviewed a prostate cancer thought leader, Dr Oliver Sartor (right) for his personal perspectives and look at the take homes from the lens of an experienced triallist in this niche.
Let’s see what he had to say about PARP inhibitors in advanced prostate cancer, as well as the PROfound and TRITON studies…
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We’ve been writing about PARP inhibitors since 2006! Who knew this target would have multiple legs over a dozen years on?
In this post we’re taking a look at some of the noteworthy presentations at ESMO19 around targeting DNA damage repair (DDR) and how they act through synthetic lethality and/or the generation of immune response to kill cancer cells in GU cancers.
It’s a fascinating area where we are seeing convergence between immunotherapy and genomic instability, one of the hallmarks of cancer.
The abstracts for ESMO19 are not yet available, so in this post we’re only providing context and setting the scene for some of the presentations we are looking forward to, as well as raising some key questions that we hope will be answered in Barcelona.
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At one point not too distant in the past, all the big news seemed to flow out of advanced prostate cancer with abiraterone and enzalutamide vying for attention, followed by occasional news on ARN–509, ODM–201, galeterone (remember that one from Tokai with all the AR-V7 kerfuffle?), radium Ra–223 dichloride, cabazitaxel, denosumab, ipilumumab, PROSTVAC, brachyury, and a few others. Predictably, not all were successful, and the count is still out on some.
In our latest conference coverage, we take a look at what we can learn from riding the prostate cancer train at ASCO GU ahead of the presentations in San Francisco tomorrow.
We will be updating this review as more data become available with the presentations, so do grab a cup of joe and settle down for some interesting reading ahead of time… this should get you all up to speed on the journey there!
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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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Red Bull Air Race NYC
San Francisco: Today at the 2018 American Society for Clinical Oncology Genitourinary Cancer Symposium, commonly known as ASCO GU (Twitter #GU18), Dr Eric Small (UCSF) will present the results of the SPARTAN phase 3 trial (Link to abstract):
SPARTAN, a phase 3 double-blind, randomized study of apalutamide (APA) versus placebo (PBO) in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC).
Despite the fact this is a positive trial and apalutumide will most likely gain regulatory approval for this indication in the United States, the data presented at ASCO GU is not a winner when viewed in the broader context of the prostate cancer landscape.
BSB subscribers can login to understand why, and also gain the perspective of a global thought leader familiar with both the SPARTAN and PROSPER trial data.
On a day when J&J have just announced that abiraterone (in combination with prednisone) provides a new treatment option for patients with metastatic high-risk castration-sensitive prostate cancer based on the results from the randomised phase 3 LATITUDE study, everyone’s attention is focused on the battle between SPARTAN (apalutamide) and PROSPER (enzalutamide) in M0 disease.
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At the inaugural event in Orlando last year, one of the highlights for me was learning how important CD38 might turn out to be as another immune checkpoint target in combination with other approaches.
This year the meeting moved to the west coast and was held in San Francisco, making it the third one this month after JPM18 and GI18. Indeed, the fourth such event is also rapidly coming up with ASCO GU next month!
So what did we learn this time around? Quite a lot it would seem.
While much of the clinical data of late associated with immune checkpoint blockade (ICB) has been in metastatic melanoma and non-small cell lung cancer (NSCLC), two other tumour types that have received increasing attention in the IO space have been clear cell renal carcinoma (ccRCC) and prostate cancer.
There were a few interesting new things we can learn here…
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Dr James Gulley is Chief of the Genito-Urinary malignancies branch and Director of the Medical Oncology service at the National Cancer Institute (NCI) in the National Institutes of Health. He’s a world-leading GU cancer expert and at the forefront of pioneering research to make cancer immunotherapy work in prostate cancer.
We last spoke to him at ASCO 2015 (See post: The future of prostate cancer immunotherapy). You can listen to excerpts from this interview on Episode 4 of the Novel Targets podcast (See: The non-inflamed tumour show).
Almost two years on, and new research by Dr Gulley and colleagues from the NCI shows that the STING pathway may have an important role to play in prostate cancer immunotherapy. Activation of this pathway through a novel mechanism could turn a cold non-inflamed tumor into a more inflamed or hotter one in men with advanced prostate cancer. How cool is that?!
At the 2017 annual meeting of the American Association for Cancer Research (AACR) that was recently held in Washington DC, Dr Gulley graciously spoke to BSB about some of the novel trials that are underway at the NCI, with the aim of making cancer immunotherapy work in men with advanced prostate cancer.
Dr Jim Gulley, NCI at AACR17
This is the seventh expert interviews in our series from AACR17 where we explore the conundrum:
How does Dr Gulley plan to light the immune camp fire in prostate cancer?
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The 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. This post is Day 3 in our Road to AACR 2016 series.
We’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.