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Posts tagged ‘Dasatinib Prostate Cancer’

It’s disappointing to learn from the ASCO 2013 GU symposium abstracts published today that Bristol Myers Squibb’s tyrosine kinase inhibitor, dasatinib (Sprycel), has failed in prostate cancer.

Dasatinib now joins a large graveyard of cancer drugs that showed promise in early clinical development in solid tumors, yet the data was not confirmed in a large scale randomized phase 3 trial.

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The phase 1 / 2 trial results for dasatinib in advanced prostate cancer were published by John Araujo, MD and colleagues last year in the journal “Cancer” (Jan 1, 2012).

The paper concluded on the basis of two trials with 46 men that “the high objective response rate and favorable toxicity profile are promising and justify randomized studies of docetaxel and dasatinib in castration-resistant PC.”

Fast forward to the dasatinib phase 3 trial results published at ASCO GU 2013, where the data from a large scale randomized trial involving 1,522 men with advanced prostate cancer showed no significant difference in survival between men receiving dasatinib plus docetaxel (chemotherapy) versus men receiving docetaxel alone. The median survival between the two treatment arms was 21.5 vs 21.2 months (HR 0.99 P=0.90).

As the FDA comes under pressure to grant approval to promising cancer drugs based on early clinical trial data, the failure of dasatinib reminds us why large randomized trials are needed to show that a drug truly works, and the potential nemesis that may occur if phase 2 hubris alone is relied upon.

The news of dasatinib’s failure in prostate cancer is a disappointing result, but does not affect it’s role in CML where it is already approved.

Update Feb 13 – dasatinib may be effective in a subset of patients

I corresponded by email today with Evan Yu, MD, Associate Professor of Medicine & Oncology at the University of Washington School of Medicine and one of the co-authors on the dasatinib abstract presented at ASCO GU 2013.

BSB: Do you have any thoughts on why the phase 1/2 trial was promising yet the phase 3 trial ends up a failure?

Dr Yu: The challenge comes from identifying patients who have tumors that are being strongly driven by SRC.  The phase 2 monotherapy data was promising, but the greatest effect was on bone turnover.  And we know that SRC is expressed on
osteoclasts.  The phase 1/2 combination docetaxel with dasatinib trial also showed promising results.  However, it was a single arm trial without randomization.  The phase 3 trial was definitely solid, well-run, and BMS should be congratulated for running such an impressive trial.

BSB: Given there was a good scientific rational for targeting Src, any thoughts on what happened from a scientific perspective that might explain the lack of any survival benefit?

Dr Yu: One must ask whether overall survival was the right endpoint for this trial?  My suspicion is that the drug has potent effects in the bone for most patients, but significant direct antitumor effect for a small subset that is yet undefined.  Hopefully, smaller translational studies down the road performing tumor biopsy analysis and quantitative fluoride PET imaging will help identify those populations.

Dr Yu’s perspective highlights the challenge of oncology drug development, where increasingly companies need biomarkers to identify those patients who are likely to respond and to monitor the response to treatment. His comments add weight to the notion that companies need to spend more time in phase 2 development before rushing to costly, large-scale phase 3 trials. If you don’t know who is likely to respond to your drug, then you run the risk that those who don’t respond will turn your trial into a negative result.

Update Feb 15, 2013 – dasatinib fails to show a survival benefit in any subgroup

There is additional commentary from the presentation of the dasatinib READY phase 3 trial results in my piece on Xconomy about the prostate cancer drug winners and losers at ASCO GU.


TBMS Sprycel Logohe results of the phase 3 clinical trial of dasatinib (Sprycel) plus docetaxel/prednisone versus placebo and docetaxel/prednisone in men with castration-resistant metastatic prostate cancer (CRPC) are expected soon.

BMS recently updated the website to show that the dasatinib phase 3 randomized prostate cancer “READY” trial (NCT00744497) of 1500 men completed data collection in August.

Data is expected before year end and, If positive, could be a late breaker at the ASCO Genitourinary Cancers Symposiusm (ASCO GU) in Orlando from Feb 14-16, 2013.

Dasatinib inhibits Src-family kinases (SFK)

Dasatinib is approved for Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia and Ph+ acute lymphoblastic leukemia (ALL). It is a BCR/ABL, LYN and Src family tyrosine kinase inhibitor.

Src-family kinases (SFK) are involved with tumor proliferation and bone metabolism.

In the phase 1 & 2 clinical trials of dasatinib with docetaxel, many of the men with prostate cancer saw a decrease in PSA from baseline, reduction in tumor size and bone scan improvement and stabilization. Encouraging early results led to the start of a phase 3 randomized trial of dasatinib in combination with the chemotherapy, docetaxel.

However, the results for Src inhibitors in prostate cancer have been mixed to date, with not all agents generating positive data. Astra-Zeneca’s saracatinib (AZD0530), for example, showed little clinical effect on its own in a phase 2 prostate clinical trial.

It has been suggested by KOLs at numerous conferences that Src inhibitors may potentially be more effective in combination with other cancer agents. Data suggests that Src might be a resistance mechanism to enzalutamide (MDV3100), so it would be interesting to see whether a dasatinib/enzalutamide combination may be more effective than enzalutamide on its own.

Meanwhile, we await the data to see whether the combination of dasatinib with docetaxel generates a significant increase in overall survival over docetaxel alone. While some are “hopeful”, Dr Oliver Sartor, Professor of Cancer Research at Tulane Medical School noted in a prostate cancer session at ESMO 2012 that, “the docetaxel-combination graveyard is big!

Update Jan 26 2013: Dasatinib Phase 3 Data at ASCO GU

Results from the dasatinib phase 3 prostate cancer trial are a late breaking abstract at the 2013 ASCO Genitourinary Cancer Symposium (ASCO GU) in Orlando. The data will be presented on February 14 by John Araujo MD PhD, Assistant Professor in the Department of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston.

LBA #8: Overall survival (OS) and safety of dasatinib/docetaxel versus docetaxel in patients with metastatic castration-resistant prostate cancer (mCRPC): Results from the phase III READY trial.

Prostate cancer is the second leading cause of cancer death in men, so it was good news this morning when Medivation & Astellas issued a press release that showed positive data from the phase 3 AFFIRM trial for MDV3100.

MDV3100 produced a 4.8-month advantage in median overall survival compared to placebo.

The estimated median survival for men treated with MDV3100 was 18.4 months compared with 13.6 months for men treated with placebo.

MDV3100 provided a 37 percent reduction in risk of death compared to placebo (Hazard Ratio=0.631).

To put the 4.8 month survival advantage in context, this compares favorably with 3.9 months for abiraterone (Hazard Ratio =0.646), in the COU-AA-301 trial.

Positive data was expected given the sound scientific rationale behind MDV3100 and the preliminary data (abstract 4501) presented at the ASCO annual meeting this year. J Clin Oncol 29: 2011 (suppl; abstr 4501).

The drug has a high affinity for the androgen receptor (AR) that is highly expressed on prostate cancer cells.  You can read an excellent interview on Pharma Strategy Blog with Charles Sawyers, who was one of the co-inventors.

MDV3011 blocks the androgen receptor (AR) from moving into the nucleus and activating growth genes and is a more complete inhibitor of AR than bicalutamide.

One hot topic of conversation at ASCO was the potential to combine MDV3100 (androgen receptor blocker) with abiraterone acetate (Zytiga) (androgen synthesis inhibitor), thereby shutting down upstream and downstream activity of the driving receptor in advanced prostate cancer.  The scientific rationale for this appears sound, so it is likely that a combination clinical trial may well be done to test this hypothesis at some point in the future.

MDV3100 has a significant advantage over abiraterone acetate (Zytiga) in that concomitant steroids are not required. Daily steroids have their side effects.  Urologists in particular will be attracted to MDV3100 and its ease of use.

Clinical trials in prostate cancer are ongoing with a multitude of new emerging therapies including TAK-700, Cabozantinib (XL184), radium-223 chloride (Alpharadin), BPX-101, Prostvac-VF, ipilumumab, Custirsen (OGX-011), dasatinib (Sprycel), lenalidomide (Revlimid) and ARN-509 to name but a few.

It is a therapeutic area with a lot going on after very little activity for a decade. The positive interim data for MDV3100 announced today is good news for prostate cancer patients, and we await presentation of the data next year.

Medivation and Astellas plan to hold a pre-NDA meeting with the U.S. Food and Drug Administration (FDA) in early 2012, so US approval could be possible later next year.

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