Update on PARP inhibitors including olaparib, iniparib and veliparib

By MaverickNY on January 28, 2011

Now that the dust has settled on the news from sanofi-aventis yesterday that iniparib did not achieve it’s primary survival endpoints in the phase III trial in newly diagnosed triple negative breast cancer (TNBC), it’s time to take stock of this class.

Yesterday was another major snow shovelling day in New Jersey so I missed the AstraZeneca year end conference call. A Pharma Strategy Blog reader kindly filled me in with some relevant information – the company discontinued the development of their PARP inhibitor, olaparib, in BRCA breast cancer – scroll down to the discontinued section to see the note.

Our source also listened to the Q+A and in response to questions on olaparib from the analysts, Martin Mackay, the Head of R&D observed that:

“We decided to focus on serious ovarian cancer, and really focus our attention to that in the first instance and wait to see how those results play out in Phase III. Then we’ll revisit… breast cancer.”

This raises some interesting questions about PARP inhibitors in general.

Yesterday, we noted the fine line that needs to be trod between potency/efficacy and tolerability. Last ASCO we saw how challenging it was to manage the toxicities with olaparib in combination with chemotherapy. Iniparib doesn’t appear to add to the adverse event profile in combination, but missed its efficacy endpoints.

Meanwhile, Abbott’s PARP inhibitor, veliparib, is being tested in the I-SPY breast cancer trial, so while it will be a while before we see any data, it will be interesting to see how it pans out given that it is also more potent than iniparib. Pfizer, BMS and Merck are also potential players in the PARP class, but their inhibitors are in earlier stage development. Based on the latest news with iniparib and olaparib it will be fascinating to see what they decide to do.

The latest developments in triple negative breast cancer also raise other critical issues:

Was the olaparib decision based on toxicities, lack of efficacy or being behind iniparib, since they recently announced their phase II results?
How will neliparib fare in the neoadjuvant setting and what toxicities might be expected?
TNBC are mainly basal cell histology so many will also be BRCA1 or 2 positive – did these women do better in the olaparib trial?
Will the Pfizer and Merck compounds have a better risk:benefit profile?
What biomarkers will emerge to indicate subsets or predict response to therapy?
If (5) does evolve, how will this develop from a diagnostics perspective?
What will happen in ovarian, lung and prostate cancers, all of which have a very small proportion of people who have the BRCA1 or 2 mutation.

The current situation with iniparib and olaparib raises more questions than answers, so it will be interesting to see what learnings emerge from the data and whether the once promising class is salvageable or dead.

All in all, 2011 is turning out to be an interesting year and we have yet to get past January.

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Sanofi's iniparib misses primary endpoints in newly diagnosed triple negative breast cancer

By MaverickNY on January 27, 2011

BREAKING NEWS

That was the essence of an email alert that landed in my inbox from sanofi-aventis just now:

“A randomized Phase III trial evaluating BSI-201 (iniparib*) in patients with metastatic triple-negative breast cancer (mTNBC) did not meet the pre-specified criteria for significance for co-primary endpoints of overall survival and progression-free survival.”

After the brouhaha of the positive phase II data published in the NEJM the other week, this is another example of we should be careful getting over-excited by early data until confirmatory larger scale study results are available.

However, while the agent flopped in newly diagnosed disease, in the relapsed/refractory setting there was a silver lining of hope:

“The results of a pre-specified analysis in patients treated in the second- and third-line setting demonstrate an improvement in overall survival and progression-free survival, consistent with what was seen in the Phase II study.

The overall safety analysis indicates that the addition of BSI-201 did not significantly add to the toxicity profile of gemcitabine and carboplatin.”

Iniparib was thought to offer the best chance of success with PARP inhibitors because the others have so far been shown to be

more potent
more challenging to combine given the toxicities involved.

Clearly it is a fine line between potency and toxicities with this particular class.

Trials are ongoing with other tumour types including lung cancer, but there may still be an opportunity for approval in triple negative breast cancer in the 2nd and 3rd line settings.

It will be interesting to see how the subset analysis pans out and whether those women who had the BRCA1 or 2 mutation fared better than those who did not.

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PI3-kinase (PI3K): a hot topic in cancer research

By MaverickNY on July 19, 2010

Recently at a couple of scientific cancer meetings, American Urology Association (AUA) and American Society of Clinical Oncology (ASCO), Frank McCormick described a fascinating talk about how a wac-a-mole approach to figuring out how the phosphatidylinositol 3′-kinase (PI3-kinase or PI3K) pathway could be targeted effectively with therapeutics. The reason for research in this area is PI3K has been shown to play a major role in proliferation and survival in a wide variety of human cancers, thus making is a potential target for therapeutic intervention.

I’ve been following this target for a couple of years now and data is now starting to emerge that’s worth discussing on a broader scale, given the implications. Here’s a quick snapshot of the PI3K pathway and related pathways:

Source: Workman et al., Nature

As many of us well know, however, simply targeting one element of an aberrant pathway can lead to cross-talk and feedback loops as the cancer tries to maintain the signals important for it’s survival, so a more cunning approach is needed whereby the escape routes are closed off one by one by targeting different kinases as well as PI3K.

McCormick’s talk was a fascinating lecture that basically went through multiple pathways explaining, ‘well we tried X and this happened, so we tried blocking Y as well and this happened…’ kind of approach in a very logical and systematic fashion. Eventually, all options will be explored and a new paradigm might emerge.

It was therefore with great interest that I read a series of new papers in AACR’s journal, Clinical Cancer Research (see references below) over the weekend on both the pathway itself, and also new data with targeted PI3K agents in both breast and renal cancers.

The Data so far:

Miron et al., looked at PI3K mutations in in situ and invasive breast carcinomas and reported:

“This is the first study to show that PIK3CA mutation is a relatively early event in breast tumorigenesis preceding invasion because the frequency of PIK3CA mutations was the same in pure DCIS as in DCIS adjacent to IDC and in IDC.”

Given the frequency of mutations was the same for the 3 groups they studied (pure ductal carcinoma in situ (DCIS), DCIS adjacent to invasive carcinoma, and invasive ductal breast carcinomas), the data suggest that the PI3K mutation may play a greater role in breast tumor initiation than in invasive progression.

If this is the case, targeting PI3K early, for example in neoadjuvant therapy, may have a positive beneficial effect.

In the O’Brien paper, the researchers looked for predictive biomarkers of sensitivity to Roche/Genentech’s PI3Ki, GDC-0941 in preclinical models of breast cancer:

“We found that models harboring mutations in PIK3CA, amplification of human epidermal growth factor receptor 2, or dual alterations in two pathway components were exquisitely sensitive to the antitumor effects of GDC-0941. We found that several models that do not harbor these alterations also showed sensitivity, suggesting a need for additional diagnostic markers.”

Identifying suitable biomarkers in preclinical studies, such as the HER2 amplification and the PIK3CA mutation (but not PTEN deficiency) previously identified in other studies and now validated in O’Brien et al’s GDC-0941 study, will hopefully help in better design of future clinical studies. They also noted that decreased ERBB3 expression in PIK3CA mutant cell lines, and ERBB3 expression was increased in response to treatment with a PI3K inhibitor, suggesting that ERBB3 expression levels might be used as a biomarker for high activation of PI3K signaling and increased sensitivity to PI3K inhibitors. This kind of rigourous approach would potentially enable selecting which people are most likely to respond up front to the agent, rather than exposing those who are unlikely to get a response to additional toxicities and side effects.

In a well written editorial, Turke and Engelman, also emphasised that:

“A novel expression profile was developed to identify other breast cancers sensitive to PI3K inhibitors. These expression studies highlighted feedback networks connecting TORC1, PI3K, and mitogen-activated protein kinase (MAPK) pathways, and underscored the potential for combination therapies.”

They also went on to observe:

“It will be interesting to determine if PI3K inhibitors induce substantial apoptosis in vitro and tumor regressions in vivo in these cancer models (without HER2 amplification or PIK3CA mutation). Of course, it will be crucial to assess biomarkers identified in laboratory studies in clinical samples from patients who respond to PI3K inhibitors. Neo-adjuvant trials in breast cancer patients can be leveraged to address these translational goals, because they correlate clinical efficacy and pathologic signs of response (e.g., changes in Ki67 levels and induction of caspase cleavage) with the presence of potential biomarkers.”

In another study, Cho et al., looked at the effects of a dual PI3-Kinase/mTOR Inhibitor
NVP-BEZ235 compared with rapamycin in renal cancer (RCC) with BEZ235 (Novartis). The proof of concept for mTOR has already been shown clinically with the approval of two drugs in this indication, temsirolimus (Pfizer) and everolimus (Novartis):

“These agents induce only modest tumor regression and extend progression-free survival only a few months in most patients.”

The big question here is whether targeting PI3K as well as mTOR would have any extra beneficial effects? The results demonstrated that dual inhibition of PI3K/mTOR with BEZ235 induced growth arrest in RCC cell lines both in vitro and in vivo more effectively than inhibition of TORC1 alone. If reproduced in the clinic, this may offer a new and more effective approach to treatment of the disease.

The Future:

The PI3-kinase field is particularly interesting, with several companies snapping up PI3K inhibitors including sanofi-aventis (from Exelixis) and more recently, Infinity (from Intellikine). Other oncology companies already have some in their pipeline, such as Novartis (BEZ235) and Roche/Genentech (from Piramed). Meanwhile, smaller biotechs such as Semafore and Calistoga also have some promising early phase compounds in development. Some of these compounds target PI3-kinase alone, while others target PI3K and mTOR.

This is not going to be a straightforward approach to targeting cancer and identifying biomarkers along the way will be key, as well working out the best combinations that might make a more effective therapeutic approach than single agent activity. Figuring out when best to test these agents (early or late) will also be critical. The I-SPY breast cancer trials have already led the way in creating protocols for testing novel agents in the neoadjuvant setting in breast cancer, and it may well be that PI3K inhibitors would be a good class to test in this setting based on the new evidence from Miron et al’s study.

What is particularly interesting to me is that PI3K signalling may also have a role to play in asthma and COPD (the area I did my doctoral research in) rather than just cancer. Now that would be really fascinating as the biochemical and molecular biology overlap have long been suspected, but very little research has really evolved this way. Part of that is due to drug manufacturer silos and the inability to effectively spearhead cross-therapeutic research.

It will be fascinating to watch how the PI3K data shakes out in practice over the next few years.

What do you think?

O’Brien, C., Wallin, J., Sampath, D., GuhaThakurta, D., Savage, H., Punnoose, E., Guan, J., Berry, L., Prior, W., Amler, L., Belvin, M., Friedman, L., & Lackner, M. (2010). Predictive Biomarkers of Sensitivity to the Phosphatidylinositol 3′ Kinase Inhibitor GDC-0941 in Breast Cancer Preclinical Models Clinical Cancer Research, 16 (14), 3670-3683 DOI: 10.1158/1078-0432.CCR-09-2828

Turke, A., & Engelman, J. (2010). PIKing the Right Patient Clinical Cancer Research, 16 (14), 3523-3525 DOI: 10.1158/1078-0432.CCR-10-1201

Miron, A., Varadi, M., Carrasco, D., Li, H., Luongo, L., Kim, H., Park, S., Cho, E., Lewis, G., Kehoe, S., Iglehart, J., Dillon, D., Allred, D., Macconaill, L., Gelman, R., & Polyak, K. (2010). PIK3CA Mutations in In situ and Invasive Breast Carcinomas Cancer Research, 70 (14), 5674-5678 DOI: 10.1158/0008-5472.CAN-08-2660

Cho, D., Cohen, M., Panka, D., Collins, M., Ghebremichael, M., Atkins, M., Signoretti, S., & Mier, J. (2010). The Efficacy of the Novel Dual PI3-Kinase/mTOR Inhibitor NVP-BEZ235 Compared with Rapamycin in Renal Cell Carcinoma Clinical Cancer Research, 16 (14), 3628-3638 DOI: 10.1158/1078-0432.CCR-09-3022

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Two new cancer drugs approved – cabazitaxel and nilotinib

By MaverickNY on June 18, 2010

Yesterday brought two new approvals in a day from the FDA in completely different cancer types.

In the morning, sanofi-aventis' cabazitaxel (Jevtana) was approved in castrate-resistant prostate cancer after failure of docetaxel (Taxotere) several months ahead of schedule. This approval comes hot on the heels of Dendreon's sipuleucel-T (Provenge) in asymtomatic metastatic prostate cancer last month.

What this means is that once androgen ablation therapies stop working, there are three new treatment options for men with prostate cancer, none of which compete with each other, with the possible exception of the chemotherapies, since docetaxel is often given in second-line in men who previously responded well and have had a treatment break. It will be interesting to see if this approach continues or if oncologists will prefer cabazitaxel in those with a good performance status.

The real impact of cabazitaxel though, is on other agents in development. Currently, abiraterone (Cougar Biotech/J&J) and MDV3100 (Medivation/Astellas) were being tested in docetaxel refractory prostate cancer, but now there is a new standard of care, whereas previously there was none. Clearly, common sense suggests that their role might be more impactful earlier in the disease, either after hormonal therapies fail, instead of or in combination with them, especially given that they are oral therapies, making them attractive to urologists.

Classic drug development usually means starting in the relapsed or refractory metastatic setting. The next few years will be thus be interesting to watch, especially if the agents in clinical trials prove successful. For now, Dendreon have a couple of years breathing space until the market potentially starts to get more crowded.

The other Priority approval yesterday was for Novartis' nilotinib (Tasigna) in newly diagnosed chronic myeloid leukemia (CML) on the basis of higher and earlier response rates versus the current standard of care, imatinib (Gleeevc). Full approval follows later once the survival data is more mature, but the early 12 month data looks interesting with a significant advantage to nilotinib over imatinib. It's still early though, survival curves can do strange things over time and can cross over.

Still, it's a promising start and a good result, especially since the bar was raised very high by imatinib. Prior to imatinib, ten year survival in CML was 10 to 20% at best with high dose interferon, but imatinib raised that dramatically to 90%. The second generation TKIs such as nilotinib and dasatinib (BMS) will thus potentially represent incremental survival improvements to 93 or 94%, to put them in context.

Of course, nilotinib's approval will possibly impact dasatinib (Sprycel) since they have just filed for the same indication, making Priority review more unlikely. The last time that happened to two drugs in the same cancer type was for Erbitux (ImClone) and Avastin (Genentech), who filed a few weeks apart, but in two different indications (newly diagnosed and 3rd line).

If dasatinib does get a Priority review after nilotinib it will set a new precedent, but if it doesn't get Priority review, I wonder if an ODAC will occur given that's usually what happens with standard 12 month review?

What's fascinating about the dasatinib data is that it also demonstrated earlier and deeper responses than imatinib, but the front-line data presented by Drs Kantarjian and Baccarani at ASCO and EHA respectively, did not appear to show any earlier survival benefit at 12 months for dasatinib vs imatinib, unlike nilotinib. I say 'appear' because the curves were very close together and no P value was given, so my assumption is that they weren't significantly different at this stage. That may change over time, but for now, the DASISION data presented by Dr Kantarjian showed a 12 month OS of 97.2% to dasatinib and 98.8% to imatinib, presumably not a significant difference. Deaths in the two arms were 10 and 6 respectively, again favouring imatinib, but not significantly.

Obviously, comparing these curves at 5 years would be a much fairer comparison for overall survival, but for now, the 12 month data is all we have to go on and there are early differences between nilotinib and dasatinib.

It was also interesting to watch the often hyped and inelegant reporting of the data by the media at the Congresses proclaiming superiority. We know that in solid tumours, shrinkage or tumour response does not always lead to an improved survival benefit for the patient. Similarly, in leukemia, we also measure response rates – in this case – complete cytogenetic response (CCyR), major molecular response (MMR) and complete molecular response (CMR), as initial surrogate markers for initial approval, but survival is also critically important for full approval in the US. Interestingly, the early log 4 reduction (CMR) rates seemed to slightly favour nilotinib over imatinib (but not significantly), however none were presented at ASCO or EHA for dasatinib over nilotinib (unless I missed the slides).

Ultimately, ASH will herald the 2-year and 18-month data for nilotinib and dasatinib respectively, which will hopefully be an important milestone on the way to seeing how the mature five year surviv
al data will evolve.< /p>

Disclosure: I'm a former Novartis employee and marketing director for Gleevec, so naturally I'm slightly biased towards imatinib :). Many thanks to @erohealth for proofreading suggestions.

#AUA2010: The beginning of a new era for prostate cancer?

By MaverickNY on May 30, 2010

Past American Urological Association (AUA) meetings have seen a lot of same old, same old with very little that is new in the way of truly innovative and exciting new developments. In many ways, prostate cancer is the male equivalent of ovarian cancer, with pharma companies considering it after the breast, lung and colorectal cancers, despite prostate cancer being fairly large in terms in epidemiology, from a pure numbers perspective.

Why is this?

Firstly, we need to consider the natural course of the disease, which unlike breast and lung cancers, is fairly indolent. Men diagnosed early with prostate cancer can live for 10-15 years, often with long periods of watchful waiting, making adjuvant trials necessarily long ones.

Secondly, once hormonal therapy begins to enable castration and reduction in the levels of testosterone that drives the cancer's growth, patients are seen and managed by urologists, who prefer to treat with oral therapies. Until recently, Pharma focused very much on intravenous infusions designed for oncologists and never the twain really met in the middle.

Thirdly, traditional drug development for chemotherapy begins in the latest stage of treatment after failure of existing therapies (typically 2nd or 3rd+ line) and moves earlier up the disease stage in a classic niche by niche development strategy.

These factors combine to essentially create 3 distinct, albeit crude, phases of treatment for prostate cancer:

Watchful waiting
Androgen deprivation therapy (ADT)
Chemotherapy for stage IV metastatic disease

How are things changing?

Dendreon recently received approval for their autologous cell vaccine, sipuleucel-T (Provenge) in asymptomatic metastatic castration resistant disease, meaning that in men where hormonal therapies cease to work but have some early evidence of metastatic disease, now have a completely new and relatively non-toxic therapeutic option prior to chemotherapy with Taxotere, mitoxantrone or even prednisone.

Much has been written about the potential for vaccines earlier in the disease when the tumour burden is much lower, so hopefully we will see some future exploration in this area now that the proof of concept for the first commercial cancer vaccine exists and Dendreon will have more funds to reinvest in R&D as revenues are generated. They have a real opportunity here.

Past studies with docetaxel (Taxotere) have shown an improved survival benefit of 2.4 months over prednisone alone in androgen independent (hormone refractory) population that was essentially symptomatic. Two phase III Provenge studies reported a median survival benefit of 4.1 and 4.5 months respectively, meaning that 50% of the men did better and 50% did worse than 4-4.5 months.

There are now at least 8 other compounds in phase III development for the treatment of advanced prostate cancer. One of these, sanofi-aventis' cabazitaxel (Jevtana) has already been filed and DDMAC review is expected in the summer, meaning the drug could possibly get approval in the 2nd-line setting after Taxotere by September in an area of high unmet need since there are few options available in this setting. The data is expected to be presented at ASCO next week, so more on that then.

So now we have two potential therapeutic options before and after Taxotere in 2010 alone, which is progress indeed.

What other compounds are there?

There are a number of agents that I like. Cougar and J&J's abiraterone is probably the most advanced. It is an inhibitor of 17,20 lyase that essentially throttle testesterone production in the testes and adrenal glands. Millennium-Takeda also have a similar compound in earlier development called TAK700. The two appear to differ in that one is steroidal and the other is non-steroidal, but whether this will make any meaningful difference isn't yet clear. Time will tell.

The abiraterone trials are not scheduled to complete until mid 2011 at the earliest, so assuming the data is positive, approval likely won't happen until the 2nd half of 2012, giving Dendreon a two year commercial advantage over the competition, who are mostly testing their compounds in the post Taxotere setting, at least initially.

Perhaps the most exciting agent from a biology perspective is MDV3100 from Medivation/Astellas, which I have written extensively about in past blog posts. Essentially, the current androgen blockers are fairly ineffective at controlling aggressive disease so a more complete inhibitor of the Androgen Receptor (AR) may offer a better chance of making an impact. Medivation have quickly realised that their real opportunity may well be either after hormonal therapies, in combination with them, or perhaps even in place of them earlier in the disease and have announced several new phase II and III trials will commence later this year. Astellas have significant advantage over J&J as a partner since they already have a strong urology franchise, which is vitally important going forward.

Several other therapies interest me too, but they will be the subject of another blog post later during this meeting as the mutations and critically expressed pathways as the disease progresses may well drive future therapeutic interventions.

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American Urology Association AUA 2010 annual meeting

By MaverickNY on May 25, 2010

On Friday, I'm heading off to the annual American Urology Association (AUA) meeting in San Francisco and looking forward to catching up on the hot topics in prostate and renal cancers.

It promises to be a good meeting this year with lots of new data expected from a number of marketed products, newly approved products and of course, products in development.

I'll be tweeting snippets from the meeting under the hashtag #AUA2010 as some attendees are already actively using that one. Unfortunately, #AUA already seems to be used for something else, which is a shame as those extra 4 characters make a huge difference on Twitter!

More to follow at the meeting, where I'll summarise some of the key findings over the weekend as they are published.

If you're attending the event and would like to meet up, please contact me either via email or via Twitter - it's always fun to meet people in real life!

Photo Credit: Alain Picard

ASCO 2010 Preview #2: PI3K and mTOR inhibitors

By MaverickNY on May 12, 2010

One of the interesting things about scientific conferences such as AACR and ASCO is that everyone looks at the same data differently as if it were through a kaleidoscope.

Brand marketers focus on their competition by tumour type or disease, scientists look at specific mechanisms or pathways, investors look at particular companies and so on.

Someone asked me the other day how I analyse the data. I hadn't really thought about it much until then, but on reflection what I'm interested in is trends and how research evolves from a big picture science view so that means I look at pathways like a true biochemist. This also teaches us where the gaps are and what opportunities may arise in the future. It's not exactly rocket science, but it is a useful approach sometimes.

Image via Wikipedia

One of the clear trends emerging at AACR the other week is that dual inhibition of both the PI3K-mTOR and RAS-ERK pathways may be necessary in some cancers such as melanoma to reduce cross-talk, feedback and feedforward loops, drug resistance and loss of PTEN gain of function, just as one might also target IGF-1R and EGFR to reduce cross-talk and add in another inhibitor, eg MEK or AKT.

Given the increasingly critical role of MEK and AKT in various combinations in the future to reduce the potential for drug resistance occurring, this bodes well for a host of companies. I wasn't, therefore, surprised to see Novartis snap up Array's MEK inhibitor (ARRY-162) given they already have an mTOR on the market (everolimus, Afinitor), two PI3-kinases in development and others including a RAS inhibitor. Having a MEK inhibitor as well may therefore give them a lot of flexibility with different combinations in multiple cancer types if this approach pans out.

Merck are also following a similar approach with their mTOR inhibitor, ridaforolimus, which they have finally grabbed commercial control of from their partner, Ariad. Let's not forget they also have an AKT inhibitor, dalotuzumab and a MEKi through their partnership with AstraZeneca to play with too.

This is all good news for several biotech companies though, if some big Pharma companies start catching onto the trend and realise they need may a PI3K-mTOR inhibitor and a MEK or AKT inhibitor to stock up in their pipeline before the field gets too crowded.

Which companies might have new and interesting data in this area?

Well, Keryx and Aeterna Zentaris, Semafore, Calistoga, Intellikine and a few others all have PI3K inhibitors in development, while Exelixis have a deal in place with sanofi-aventis for XL147 and XL765 and Roche/Genentech have a pan-PI3K inhibitor, GDC-0941. Novartis have two (BEZ235 and BKM120). Some of these compounds are single PI3K inhibitors and some are dual inhibitors of PI3K-mTOR.

Looking at the ASCO abstract titles, Exelixis appear to have the most abstracts in this area this year, so it will be interesting to see what sort of data they have across a range of different tumour models and early phase I results in solid and hematologic malignancies, with a variety of different combinations.

One session I'm really looking forward to at this year's ASCO is a Clinical Science Symposium entitled, "Paths for Clinical Development of PI3K Inhibition" with some of the heavyweights in the field such as Neil Rosen (MSKCC), Skip Burris (Sarah Cannon), Jose Baselga (Spain) and Carlos Arteaga (Vanderbilt). Arteaga is presenting a talk in that session entitled, "Next steps in clinical development of PI3K inhibitors?"

More later on this blog after the posters and the data become available at the meeting.

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New developments in castration resistant prostate cancer – MDV3100

By MaverickNY on April 15, 2010

Last night I received an alert from Medivation announcing that an article would be published in today's online The Lancet regarding their prostate cancer agent, MDV3100. Sure enough, here's the article:

Although the trial is an early phase I/II study, encouraging antitumour effects were reported in 140 men, of whom 65 were chemotherapy naïve. Time to disease progression (TTP) was 47 weeks, which is decent considering the men in the study were all castration resistant and likely had advanced disease.

Obviously, it is too early to tell yet quite what Medivation and Astellas have here, but to put things in context, docetaxel (Taxotere), was approved for hormone refractory prostate cancer (HRPC) with prednisone in androgen independent (hormone refractory) metastatic prostate cancer with a median overall survival of 18.9 months (approx. 85 weeks) in a large phase III trial.

We must also remember that in another more recent trial, it was demonstrated that men who received cabazitaxel (sanofi-aventis' follow on taxane to docetaxel) lived a median of 15.1 months (68 weeks), compared with 12.7 months (57 weeks) for those who receive mitoxantrone, a difference that was statistically significant.

That said, the side effect profile of chemotherapy is certainly not benign, with significant risk of myelosuppression and infectious complications.

However, what was encouraging about the Medivation trial was early Kaplan Meier response curves, which demonstrated those men who had no previous chemotherapy generally did better than those who received it in terms of both PSA and radiological progression.

At the AACR Molecular Targets meeting last November, Charles Sawyers gave a keynote talk on prostate cancer and looked at the various opportunities for investigating new therapeutics in clinical trials for prostate cancer. He suggested that circulating tumour cells (CTCs) might be a more useful marker for disease status than PSA. In The Lancet study, the authors noted that:

"We recorded early post-treatment conversions from unfavourable to favourable in 75% of patients not exposed to chemotherapy and in 37% of those who were exposed. Decreases in PSA were generally associated with parallel falls (or no progression) in CTCs, but this finding was not consistent, suggesting that these measures assess different aspects of the malignant process. PSA decreases might in some cases be an indicator of the mechanism of action of MDV3100 as an androgen-receptor antagonist rather than an actual antitumour effect. However, the benefit of MDV3100 on several assessments, including CTCs and radiological time to progression, suggest that MDV3100 does have a true antitumour effect."

The other interesting observation that Sawyers made was that traditionally, early prostate disease is treated with oral hormonal therapies and once castration resistance sets in, the patient is referred to an oncologist for consideration of chemotherapeutic options. With the advent of new therapies with different MOAs in development such as MDV3100, abiraterone (Cougar/J&J) and Provenge (Dendreon), the lives of men with prostate cancer can potentially be extended further before stage IV metastases sets in.

At AACR last November, Sawyers also discussed the importance of androgen receptor signalling in the disease (previously discussed here with simple models) and the data from this trial seem to bear out his elegant theory. I'd like to see more analysis though and learn whether those men who had AR amplified prostate cancer did better on MDV3100 than those who did not?

All in all, this is an exciting time for men with prostate cancer. Dendreon's Provenge may well be the first new drug that fits between the hormonal therapies and chemotherapy, since the FDA PDUFA date is May 1st, although since that is a Saturday, we may well here the Go/No Go news on Friday 30th April.

In the meantime, the annual AACR meeting in DC this weekend can't come soon enough!

Scher, H., Beer, T., Higano, C., Anand, A., Taplin, M., Efstathiou, E., Rathkopf, D., Shelkey, J., Yu, E., & Alumkal, J. (2010). Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1–2 study The Lancet DOI: 10.1016/S0140-6736(10)60172-9

The potential for PI3K pathway inhibitors in lung cancer

By MaverickNY on April 12, 2010

Life is about stories, events and even coming back full circle sometimes. I experienced that moment of déjà vu this morning on opening a link to an article that a colleague kindly sent from Avrum Spira’s lab that was published in Science Translational Medicine, simply titled:

Airway PI3K Pathway Activation Is an Early and Reversible Event in Lung Cancer Development

Many moons ago I completed my doctoral thesis on the early detection of lung disease at King’s College London. Much of it was about the impact of smoking on the airways. Halfway through the 3 year MRC grant, while listening to some evening lectures at the Brompton Hospital by Prof Peter Barnes and Steven Holgate, I realised that the real answer lay in understanding the biochemical and molecular biology pathways… only we were working on the physiology of breathing patterns. An a-ha moment to be sure.

Still, I was able to pick up differences in breathing patterns between healthy non-smokers and those who were medium to heavy smokers.

The unaswered question, though, was why?

Prof Barnes loved to put up charts of pathways with a black background and different targets meticulously coded with coloured highlighter pens… PDE, leukotrienes, cholinergic mast cell activation and many others sprang to life as he walked students through the various possible mechanisms where pharmaceutic intervention might have a role to play.

Fourteen years on, I don’t think a cure for asthma has been found and many of those pathways have not yielded much in chronic obstructive pulmonary disorder (COPD) either, except perhaps anti-cholinergics such as tiotropium bromide (Spiriva) as maintenance therapy in controlling bronchospasm. My suspicion at the time was that the mechanisms underlying inflammation and aggravation of the airways by chemicals was key to unlocking why some people get lung cancer, others COPD and still others were unaffected.

Fast forward to the article.

Last week, Gustafson et al., published a paper in Science Translational Medicine suggesting that phosphatidlyinositol 3-kinase (PI3K) pathway activation is an early event in the development of lung cancer.

In particular, they found elevated PI3K in the airways of smokers with lung cancer compared to smokers without lung cancer:

Source: Science Translational Medicine

The researchers validated their hypothesis that activation of PI3K is an early event in the development of lung cancer by comparing the cytology of airway epithelium from healthy smokers to those with mild to moderate airway dysplasia that reflects an early noncancerous abnormality, often considered a precancerous state. The theory being that if smokers with dysplasia have higher PI3K pathway activation then this would suggest P13K pathway activation precedes the development of lung cancer.

The results showed increased expression of genes induced by PI3K pathway in high risk smokers and those with lung cancer. This may well explain the dysplasia and inflammation seen, which you can see in the chart below:

Source: Science Translational Medicine

One key question this research raises, but does not answer, is whether P13K pathway inhibitors have a role to play in the treatment of lung cancer?

Thinking about my doctoral research on early detection of lung disease, this statement made me sit up and pay attention:

“These results suggest that deregulation of the PI3K pathway in the bronchial airway epithelium of smokers is an early, measurable, and reversible event in the development of lung cancer and that genomic profiling of these relatively accessible airway cells may enable personalized approaches to chemoprevention and therapy.”

Whoa! Early detection of lung cancer?

Forgive my excitement and enthusiasm, but it’s kind of cool to see read that scientists can actually find something biochemically active that may represent a new target for intervention fifteen years after you realise that early detection might be possible, if only you knew what the target might be. That’s the stuff of <goosebumps.

PI3-kinase is a fascinating target that quite a few biotech and pharma companies are looking at as a potential mechanism for the treatment of cancer. I’ve written and blogged extensively on this (see here, here, here, here and here) for some examples.

Interestingly, many of the PI3-kinase compounds in early clinical development are investigating the agents in leukemias, lymphomas, breast, ovarian and gastric cancer or basket solid tumour trials. Some of the interesting small biotech companies in this field include Calistoga, Semafore and Exelixis and big pharma is represented by Merck, Novartis, sanofi-aventis and Roche. Only two agents seem to be specifically looking at non-small cell lung cancer (NSCLC) though – no prizes for guessing which ones:

Everolimus (Novartis), a combined mTOR-PI3 kinase inhibitor, in phase II development.
GDC-0941 (Roche/Genentech), which is looking at whether the new agent adds anything to the current standard of care in NSCLC ie carboplatin + paclitaxel + bevacizumab and is currently recruiting patients.

Novartis (a client) have completed their trial according to the clinical trials database, so it will be interesting to see if there are any data at ASCO in June that will help us learn more about the disease.

If the data from the Novartis or Roche trials are positive, the companies may be very interested to read Gustafson et al.’s suggestion:

“Our work further suggests that additional lung cancer chemoprevention trials either targeting the PI3K pathway or measuring airway PI3K activation as an intermediate endpoint are warranted.”

Chemoprevention is a big word in cancer research.

In two weeks time, I’ll be at the AACR annual meeting in DC (do let me know if you are going and would like to meet up for a coffee and chat) and hopefully there will be more about this fascinating pathway then. Watch this space!

Gustafson, A., Soldi, R., Anderlind, C., Scholand, M., Qian, J., Zhang, X., Cooper, K., Walker, D., McWilliams, A., Liu, G., Szabo, E., Brody, J., Massion, P., Lenburg, M., Lam, S., Bild, A., & Spira, A. (2010). Airway PI3K Pathway Activation Is an Early and Reversible Event in Lung Cancer Development Science Translational Medicine, 2 (26), 26-26 DOI: 10.1126/scitranslmed.3000251

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J&J's abiraterone shows promise for advanced prostate cancer patients

By MaverickNY on February 18, 2010

New results from a phase II clinical trial of the prostate cancer drug abiraterone suggest that it may help men with advanced disease who have tried standard treatments.

However, a Cancer Research UK clinician cautioned that there were still questions to be answered from ongoing studies about how best to use the drug.

Abiraterone was discovered in the Cancer Research UK Centre for Cancer Therapeutics at The Institute of Cancer Research (ICR) and is taken once a day as four pills.

The latest trial, which was led by the ICR and the Royal Marsden NHS Foundation Trust, is the first to investigate the drug in men with such advanced prostate cancer.

A total of 47 men were recruited for the trial, all of whom had late-stage castration-resistant prostate cancer, which means that their disease was advanced and their tumours were no longer responsive to androgen deprivation therapy. In almost all cases, the men's cancer had spread to their bones.

All of the participants had already received hormone therapy and the chemotherapy drug docetaxel, but were no longer responding to those treatments.

By the end of the study period, researchers found that around three-quarters of men had experienced a drop in levels of prostate specific antigen (PSA), which is often raised in men with prostate cancer and can be used to measure disease activity.

In around half of the men, PSA levels fell by at least 50 per cent, while three-quarters of participants also had a drop in the number of tumour cells circulating in their blood.

Three years after the start of the trial, five of the patients were still taking abiraterone and benefitting from the treatment.

via info.cancerresearchuk.org

New phase II data on abiraterone was reported this week in the Journal of Clinical Oncology from the researchers at the Royal Marsden.

Standard chemotherapy with docetaxel (Taxotere) improves survival by 2 to 3 months, so if the 6 months seen with abiraterone is repeated in a phase III trial, Johnson and Johnson (J&J) and Cougar could well have an approvable drug on their hands. The other benefit is that the side effect profile is much milder than chemotherapy, which can cause severe myelosuppression in the majority of patients receiving it.

It should be noted that these are advanced patients who have received already several hormonal therapies. The data from this trial will likely provide impetus for larger scale phase III trials, which could be used to seek regulatory approval from the US and EU authorities.

It is, however, obvious that the investigators are unsure yet what role and where abiraterone will eventually be used in the treatment paradigm, but traditional research approaches require that trials investigate advanced disease and then more up the continuum as more data and experience with the treatment is gained.

Of course, there is no guarantee that phase III trials will mirror promising phase II results, especially in the cancer arena, but now, it's nice to report on positive data after a bad run of disappointing trials in oncology of late.

Source: JCO (Abstract)

Posted via web from sally church's posterous

Reid, A., Attard, G., Danila, D., Oommen, N., Olmos, D., Fong, P., Molife, L., Hunt, J., Messiou, C., Parker, C., Dearnaley, D., Swennenhuis, J., Terstappen, L., Lee, G., Kheoh, T., Molina, A., Ryan, C., Small, E., Scher, H., & de Bono, J. (2010). Significant and Sustained Antitumor Activity in Post-Docetaxel, Castration-Resistant Prostate Cancer With the CYP17 Inhibitor Abiraterone Acetate Journal of Clinical Oncology DOI: 10.1200/JCO.2009.24.6819

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