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Update on denosumab and SRE’s: data from the 147 trial

By MaverickNY on May 17, 2011

A little over ten years ago, I lost my Father to metastatic prostate cancer, a brave fight that lasted only a few years since he was diagnosed with stage IV disease. In many ways though, it was a bittersweet moment because while it’s always heartbreaking to lose a parent, it was also a blessing that he was spared of any further pain. In those days, the only bisphosphonates available in the UK were pamidronate (Aredia) and the awful clodronate. The urologist managing my Father had no clue about either, so he suffered in silence instead.

I tell this story because, while difficult to discuss, sometimes we forget the importance of supportive care and pain management in improving the quality of life for patients with advanced cancer.

AUA 2011 DMAB SRE

Based on my family’s experience, I can tell you that it makes a huge difference, not just to the patient, but also for other family members. There is nothing more distressing to see someone in considerable pain from bone destruction and the doctors not doing anything about it because ‘it’s normal for the condition’ or they are considered ‘too old over 65’. In the end, I suspect many give up the fight because the pain becomes unbearable.

Since my Father’s passing, clinical advances in managing skeletal related events (SREs) and bone pain have thankfully moved on with the approval of another more potent bisphosphonate, zoledronic acid (Zometa) and a RANK-L inhibitor, denosumab (Xgeva). Both of these therapies increase the time to SREs associated with metastases compared to placebo, but what about bone metastases and survival – do they make any difference?

New clinical data now available

This morning at the AUA annual meeting, data was presented by Dr Matthew Smith (Mass General) on the much awaited update on the 147 phase III trial in the late breaking plenary session. The study compared denosumab (120 mg subcutaneously taken monthly) to placebo.

AUA DMAB 147 symptomatic metastases

Overall, in terms of efficacy, denosumab significantly:

– Increased bone metastasis-free survival by a median of 4.2 months compared with placebo ie 29.5 and 25.2 months, respectively (hazard ratio [HR] 0.85; 95% CI: 0.73, 0.98; P=0.028; risk reduction of 15%)

– Delayed time to first bone metastasis compared with placebo (HR 0.84; 95% CI: 0.71, 0.98; P=0.032; risk reduction of 16%)

– Delayed time to symptomatic bone metastasis (HR 0.67; 95% CI: 0.49, 0.92; P=0.01).

However, it wasn’t all good news on the efficacy front though.

Median overall survival was similar between groups (HR 1.01; 95% CI: 0.85, 1.20; P=0.91).

In other words, patients did not live longer when given denosumab therapy compared to placebo.

Comparison of side effects

Overall, rates of adverse events (AEs) and serious AEs were generally similar between groups, with two exceptions, namely:

– Yearly cumulative incidence of osteonecrosis of jaw was similar to rates previously reported for monthly denosumab 120 mg (year 1: 1.1%, year 2: 2.9%, year 3: 4.2%), although the overall cumulative rate was 4.6% (n=33).

– Hypocalcemia occurred in 1.7% (n=12) denosumab and 0.3% (n=2) placebo patients.

To put this in context, in the zoledronic acid versus placebo trial, both ONJ and hypocalcemia were lower than that seen in the denosumab study. According to Medscape Reference, this is not a side effect to be trifled with, since it can cause stroke and cardiopulmonary effects:

“Depending on the cause, unrecognized or poorly treated hypocalcemic emergencies can lead to significant morbidity or death.”

Clearly, some of the effects can be mitigated with calcium and vitamin D supplementation, although some patients, especially though with co-morbidities, may be challenging with adherence and compliance.

A critical question is are surrogate measurements clinically meaningful?

Dr Oliver Sartor raised this issue recently in a Nature publication, essentially challenging whether SRE was clinically meaningful or not, and arguing that better measurements would be a reduction in pain or improvement in the patient’s quality life when considering whether a therapy had an impact or not.

You can find out more about Dr Sartor’s insights in a recent blog post my colleague, Pieter Droppert, posted on Biotech Strategy Blog in the run-up to the AUA meeting.

In order to get to the bottom of this dilemma, I interviewed Dr Neal Shore, a urologist at the Carolina Urologic Research Center, and asked him what he thought of the significance of the data:

“This is a huge milestone in our understanding of the bone microenvironment”

On managing the adverse events versus the improved time to bone-free metastasis, Dr Shore replied,

“I think the risk benefit of preventing a skeletal metastasis versus the small, but albeit statistically real risk of ONJ, far outweighs that risk.”

The interview with Dr Shore will post tomorrow morning as a podcast as part of the Ongoing Making a Difference series – do check back to hear his insights on the 147 trial.

References:

Sartor, O. (2011). Denosumab in bone-metastatic prostate cancer: known effects on skeletal-related events but unknown effects on quality of life Asian Journal of Andrology DOI: 10.1038/aja.2011.33

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A vlog update on advanced prostate cancer from the AUA 2011 meeting

By MaverickNY on May 16, 2011

After attending numerous basic research and clinical updates at the American Urologic Association (AUA) annual meeting in Washington DC, it is clear that the new and emerging therapies are not going to stop at the three grand crus from 2010.

Recently, abiraterone acetate (Zytiga) was approved, but there are a number of critical issues that need to considered, including:

Sequencing
Combinations
Cost
Patient selection

As we learn more about the molecular mechanisms behind resistance to androgen receptor signaling (up and downstream) and new targets emerge, so it may be possible to improve patient outcomes in castration-resitant prostate cancer.

Here’s a short video update of what I thought was interesting here at the conference:

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On RANKL and denosumab in advanced cancer metastasis

By MaverickNY on March 2, 2011

In this week’s Nature, my eye was drawn to a Letter from Tan et al., (2011) discussing how inflammatory mechanisms influence tumorigenesis and metastatic progression, even in tumours that seemingly don’t involve pre-existing inflammation or infection such as breast and prostate cancers.

In advanced prostate cancer, metastasis is sadly inevitable. So far as we know, lymphocytes infiltrate the tumour, causing upregulation of nuclear factor-KappaB (RANK) ligand (RANKL) and lymphotoxin (see Luo et al., 2007).

RANK signalling controls osteoclastogenesis and bone resorption and targeting it with denosumab has been shown to reduce the incidence of skeletal related events (SRE) but not overall survival in prostate cancer (see Fizzazi et al., 2011):

and other advanced cancers, including multiple myeloma (see Henry et al., 2011). Overall survival was again not improved compared with zoledronic acid, as you can hear from this short podcast or read the accompanying editorial in the JCO from Dr Jack West of Swedish on the topic, which was both fair minded and well written, discussing additional factors that need to be considered, including costs, something that is all too often swept under the carpet.

What is less well known, however, is the source of RANKL and it’s role in metastasis. Tan and colleagues therefore decided to take a closer look at this.

What did they do?

In their research, Tan et al., (2011) decided to evaluate whether RANKL, RANK and IKK-a (nuclear factor kinase-alpha) are involved in cancer metastasis. IKK-a is a protein kinase needed for the self renewal of cancer progenitors. The question is, how do all these relate? They used various cell lines and models to explore the relationships.

The NF-kB pathway looks like this:

What did they find?

The results showed that RANK signalling in cancer cell lines overexpressing Erbb2 (HER2) was important for pulmonary metastasis. This is also potentially relevant to breast cancer, since HER2 is frequently overexpressed in metastatic disease.

Using MT2 cells in Ragl-/- mamary glands, they looked at whether RANKL was involved in metastatic spread. Most RANKL-producing T cells expressed forkhead box P3 (FOXP3), a transcriptional factor produced by T cells and were located next to stromal cells.

In all, the authors concluded that:

“Targeting RANKL-RANK can be used in conjunction with the therapeutic elimination of primary breast tumours to prevent recurrent metastatic disease.”

The challenge here though, is that while the preclinical models are very appealing in theory, in the clinic we must not forget that a significant reduction in SRE does not necessarily mean that patients live longer, as witnessed by the lack of OS benefit in the trials mentioned above.

References:

Tan, W., Zhang, W., Strasner, A., Grivennikov, S., Cheng, J., Hoffman, R., & Karin, M. (2011). Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL–RANK signalling Nature, 470 (7335), 548-553 DOI: 10.1038/nature09707

Luo JL, Tan W, Ricono JM, Korchynskyi O, Zhang M, Gonias SL, Cheresh DA, & Karin M (2007). Nuclear cytokine-activated IKKalpha controls prostate cancer metastasis by repressing Maspin. Nature, 446 (7136), 690-4 PMID: 17377533

West, H. (2011). Denosumab for Prevention of Skeletal-Related Events in Patients With Bone Metastases From Solid Tumors: Incremental Benefit, Debatable Value Journal of Clinical Oncology DOI: 10.1200/JCO.2010.33.5596

Henry, D., Costa, L., Goldwasser, F., Hirsh, V., Hungria, V., Prausova, J., Scagliotti, G., Sleeboom, H., Spencer, A., Vadhan-Raj, S., von Moos, R., Willenbacher, W., Woll, P., Wang, J., Jiang, Q., Jun, S., Dansey, R., & Yeh, H. (2011). Randomized, Double-Blind Study of Denosumab Versus Zoledronic Acid in the Treatment of Bone Metastases in Patients With Advanced Cancer (Excluding Breast and Prostate Cancer) or Multiple Myeloma Journal of Clinical Oncology DOI: 10.1200/JCO.2010.31.3304

Fizazi K, Carducci M, Smith M, Damião R, Brown J, Karsh L, Milecki P, Shore N, Rader M, Wang H, Jiang Q, Tadros S, Dansey R, & Goessl C (2011). Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet PMID: 21353695

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Some additional thoughts on Zometa in early breast cancer

By MaverickNY on December 10, 2010

Yesterday’s news from the AZURE trial at the San Antonio Breast Cancer Symposium generated a lot of buzz. I posted the data after the press briefing in the afternoon here but have received a lot of questions from people confused by the press coverage of the data. To be fair, the physician presenting the data, Dr Robert Coleman, didn’t help matters by stating:

“Clearly our results are very different from those published by the ABCSG investigators”

when referring to the previous study published in the NEJM in February last year, without elaborating clearly on the differences. Dr Coleman also stated that it was “a negative trial”.

Interestingly, in the panel disclosures only Dr Giordano from MD Anderson revealed nothing to declare; Drs Coleman (Novartis and Amgen), Chlebowski (Novartis and Amgen) and Gnant (Novartis, Amgen and AstraZeneca) all received industry funding of some kind.

For those of you interested in the detail, I included the journal reference and the differences between the two trials in the post yesterday.

But to simplify – they are actually two very different trials – involving different stages of disease, menopausal status and different base treatments, so in reality, we should not expect them to be the same, since the populations are different.

Here’s a quick summary in the table below:

Recent Zometa trials in early breast cancer-2012-01-07
What we can see from this is that the stage II/III premenopausal women who received chemotherapy did not do well on zoledronic acid, but the other two groups did. I should point out that the post menopausal subset group who did benefit were typically more than 5 years post menopause and amounted to around one third of the study participants, so it was not an insignificant number. Lumping both menopausal ER+ subgroups together for the purpose of an overall analysis is fraught with challenges given the potential heterogeneity if the two behave differently, thereby effectively cancelling each other out.

We can also see that comparing the premenopausal groups in the two trials is not an easy comparison since one received hormonal therapy and the other chemotherapy. Taking hormonal therapy essentially induces early menopause, so this means that the ABCSG trial participants may actually model the AZURE postmenopausal women closer than people realise.

The whys and wherefores will not doubt follow in due course from the breast cancer oncologists.

My only surprise in all this is that Novartis have already stated they are withdrawing the filing, which may be a little hasty given that they have 2 out of 3 positive subsets of women with breast cancer who appear to significantly benefit from zoledronic acid treatment.

Ah well, time will tell where this controversy will lead!

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Zoledronic acid did not improve disease free survival in early breast cancer

By MaverickNY on December 9, 2010

Wow, every now and then, something unexpected turns up and makes you stop, listen and most importantly, think. This was the headline from an American Association of Clinical Research (AACR) news release that I received from the San Antonio Breast Cancer Meeting (SABCS) this afternoon.

The result is totally unexpected. Why?

Well, we know the drug is effective in Stage IV metastatic disease and a previous trial from the Austrian group (study ABCSG XII) had positive results in stage I pre-menopausal women with breast cancer (see reference below). Early last year that trial was hailed as an important landmark study in The New York Times.

The current trial (AZURE) with zoledronic acid (Zometa) as adjuvant therapy in women stage II/III breast cancer was therefore expected to be positive, sitting neatly in the middle of the two previously published and positive settings.

Let’s take a look at the trial design.

3,360 women from several countries (the majority from the UK, Eire, Australia and Spain) were randomised to receive standard chemotherapy (physician’s choice), with one group receiving zoledronic acid and the other not. The women either had node positive (N+) adjuvant or T3/T4 or confirmed N+ neoadjuvant disease. They had undergone tumour resection, but not received bisphosphonates over the previous year or had any evidence of metastases. In the zoledronic acid arm, it was given as a 4mg infusion over a total of 5 years – ie 6 doses every 3-4 weeks with chemotherapy, then 8 doses every 3 months followed by maintenance therapy every 6 months for 5 cycles.

The primary endpoint of the study was disease free survival (DFS) with invasive DFS (IDFS) as a secondary endpoint. According to my notes, the planned final analysis was due to take place at 940 DFS events with an anticipated 3 year DFS of 75%, allowing for a 3 year recruitment period and 6 years of follow-up. The study was powered at 80% (two sided) to detect a 17% hazard reduction in DFS (HR=0.83) i.e. from 75% to 78.7% for DFS at 3 years. There was an original interim analysis in 2008 but the Data Monitoring Committee (DMC) did not recommend stopping the trial at that point. A second analysis was proposed (accepted) to the DMC given the low event rate for the whole study with a 3-year DFS rate of approximately 85%. The patients in both arms were well balanced for the key factors (lymph nodes, T stage, ER and menopausal status):

The groups were also well balanced for prior treatment, including chemotherapy:

The median follow-up period was similar in both groups (58-60 months), as was time since last follow-up (approx. 6 months). There was little difference between the groups in adverse events, with the exception of osteonecrosis of the jaw (ONJ), a known side effect of bisphosphonate treatment:

At this point, things started to get interesting. Here’s what happened in the ABCSG XII trial from Gnant et al.; you can see the clear separation of the DFS survival in their large (n=1803 ) trial in premenopausal women:

This is exactly what the investigators hoped to see with zoledronic acid in the AZURE trial. Instead, the survival curves virtually surprisingly overlap:

Just in case anyone is wondering whether prior bisphosphonate therapy affected the results, the analysis suggested otherwise:

As Rob Coleman, the British PI of AZURE stated in the AACR press conference, the results between the two studies are essentially ‘chalk and cheese’, meaning polar opposites:

When they looked at the AZURE subgroup analysis, they found something interesting. While the premenopausal patients saw no benefit from zoledronic acid therapy, there was a significant difference for older women (>60yo) who were postmenopausal:

Given the disparity between the ABCSG XII and AZURE trials in premenopausal women, it is hard to imagine bone studies essentially being right, creating an interesting controversy as to why there is a disparity. Bear in mind that the Austrian study was in women with stage I breast cancer without chemotherapy, while AZURE was stage II/III disease with chemotherapy. Zoledronic acid in the Austrian trial was given at the same dose (4mg), but on a much simpler schedule (every 6 months) because there was no chemotherapy involved, only endocrine treatment.

Clearly something interesting is going on in the tumour microenvironment rather than the host and further research is likely to be ongoing to try and explain the science behind these findings.

Coleman speculated that there might be increased turnover and endocrine changes going on associated with menopausal and bone cell function, but that is just a hypothesis at this stage. My initial reaction is this does not explain the ABCSG XII results in stage I premenopausal women.

Impact of the AZURE results:

Given the resoundingly overall negative outcome in DFS, it is likely that Novartis will withdraw the expanded Zometa approval to prevent breast cancer relapse. Meanwhile, there will be much controversy and discussion to try and reconcile the results of the AZURE vs ABCSG XII trials in the premenopausal setting.

I think that it is unlikely that the guidelines will support routine use of zoledronic acid in this setting, although the findings in postmenopausal women will no doubt deserve further analysis in the coming months.

Disclosure:

I’m a former employee of Novartis and also a consultant, but have never worked on Zometa.

{UPDATE}

Novartis have announced that they are indeed with drawing the filing for Zometa, with the following statement:

“Last year, Novartis filed supplemental marketing authorization applications for the adjuvant treatment of premenopausal women with HR+ early breast cancer in conjunction with hormonal therapy in the US and European Union (EU) based on the results of ABSCG-12. Novartis is currently reviewing the data from the AZURE trial results, which were expected to be added to the submission. In the meantime, Novartis will withdraw the current marketing applications and discuss next steps with health authorities.”

References:

Gnant, M., Mlineritsch, B., Schippinger, W., Luschin-Ebengreuth, G., Pöstlberger, S., Menzel, C., Jakesz, R., Seifert, M., Hubalek, M., Bjelic-Radisic, V., Samonigg, H., Tausch, C., Eidtmann, H., Steger, G., Kwasny, W., Dubsky, P., Fridrik, M., Fitzal, F., Stierer, M., Rücklinger, E., & Greil, R. (2009). Endocrine Therapy plus Zoledronic Acid in Premenopausal Breast Cancer New England Journal of Medicine, 360 (7), 679-691 DOI: 10.1056/NEJMoa0806285

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Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts tagged ‘zoledronic acid’

A vlog update on advanced prostate cancer from the AUA 2011 meeting

Some additional thoughts on Zometa in early breast cancer

Zoledronic acid did not improve disease free survival in early breast cancer