PARP inhibitors for PTEN-mutant cancer cells

Most GBM tumors (IDH1 wild-type) have a loss of one copy of chromosome 10.  Additionally, about 30% will also have a deactivating mutation in the remaining copy of PTEN, leaving no functional PTEN in these tumors.

In these tumors, PARP inhibitors may be an effective therapeutic option, based on a study showing therapeutic effects of olaparib in PTEN-negative HCT116 colon cancer xenografts, while HCT116 xenografts with restored PTEN didn't respond to olaparib.

These results are not necessarily generally applicable, as the HCT116 line is also known to have mismatch repair defect (loss of MLH1), so there may have been some interaction between loss of both mismatch repair and PTEN that sensitized cells to olaparib.

Study title:
Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors
Full study available here

SNO summary, episode 1: CeTeG trial (CCNU + TMZ versus TMZ alone)

Phase III trial of CCNU/temozolomide (TMZ) combination therapy vs. standard TMZ therapy for newly diagnosed MGMT-methylated glioblastoma patients: the CeTeG/NOA-09 trial presented by Ulrich Herrlinger for the Neurooncology Working Group (NOA) of the German Cancer Society.

The summary below written by SW, who was in attendance at the presentation by Ulrich Herrlinger and took photos of the slides presented.

The CeTeG trial (also known as NOA-09) is a randomized phase 3 trial for newly diagnosed glioblastoma with methylated MGMT promoter, testing CCNU (lomustine) combined with temozolomide (TMZ) versus TMZ alone. This trial was conducted at 17 centers in Germany and was a follow-up to a non-randomized phase 2 trial which had results published in 2006 and 2009. The CeTeG trial was relatively small for a phase 3 trial, with a sample size calculation of 128 patients total, and this sample size was based on expectations of a significant increase in survival rate at 2 years as seen in the phase 2 trial compared to historical controls. 

Patients in this trial had relatively good prognosis, with high rates of complete resection and high average KPS.  Overall the arms were well balanced, with the only significant imbalance between the two arms being gender, which was not prognostically relevant.

In the combination arm receiving CCNU + TMZ, cycles were 6 weeks in length, with 100 mg/m2 oral CCNU given on day 1 of each cycle and TMZ on days 2-6 of each cycle, with a starting TMZ dose of 100 mg/m2 and possible escalation up to 200 mg/m2 in later cycles. Cycle 1 starts at the same time as radiation.

In the control arm of TMZ alone, cycles were 4 weeks in length, and used the standard TMZ schedule (daily at a dose of 75 mg/m2 during radiation, and 150 mg/m2 on days 1-5 of the first adjuvant cycle and possible escalation up to 200 mg/m2 in later cycles.

Importantly, this trial achieved its primary endpoint of increased overall survival. Survival in the CCNU + TMZ arm was statistically superior to TMZ alone, with a p value of 0.049.  Hazard ratio for death from any cause was 0.6 in the CCNU + TMZ arm.

Median reported survival was 46.9 months for CCNU + TMZ versus 30.4 months for TMZ alone, a difference of 16.5 months.  As seen in the Kaplan-Meier survival estimates, the curves did not separate until after the 2 year mark.  1, 2, 3, 4, and 5 year survival rate was 88.8, 71.4, 57.4, 48.8 and 34% in the CCNU + TMZ arm versus 84.4, 65.4, 42.3, 31.4 and 27.7% in the TMZ arm.  Differences in the survival rate between the two arms were greatest at the 3 and 4 year mark, with 15% more patients surviving to 3 years and 17.4% more patients surviving to 4 years in the combination arm versus the TMZ alone arm.

Given the significant overall survival differences, it's surprising to note that progression-free survival was not significantly different between the two arms (p=0.41), although the progression-free survival curves separated somewhat at about 2 years (a phenomenon also seen in the overall survival curves), after which time CCNU + TMZ shows a slight superiority over TMZ alone. Some potential explanations given by the authors for the lack of a strong PFS signal included: "problems with PFS assessment according to RANO?" including potential undetected pseudoprogressions; and "long-term effects of CCNU?", noting that in studies of low grade gliomas treated with CCNU, responses were sometimes seen months or years after the end of therapy.

  

The percentage of patients receiving further lines of therapy after progression was similar in both arms (59.1% in the CCNU + TMZ arm, 63.5% in the TMZ arm).  More patients underwent re-resection in the CCNU + TMZ arm (31.8% versus 22.2%), and more patients received re-irradiation in the TMZ alone arm (23.8% versus 18.2%). More patients in the TMZ alone arm received further chemo or targeted agent therapy (60.3% versus 48.5%).  The percentage of patients receiving bevacizumab after progression was similar in both arms (27% in the TMZ alone arm, 30.3 % in the TMZ + CCNU arm).  The authors concluded that differences in treatment after progression are not an explanation for the superior survival in the TMZ + CCNU arm.

Combination therapy with TMZ + CCNU approximately doubled the rate of low-grade (but not high-grade) hematoxicity (including neutropenia and thrombocytopenia) and nausea.  However no deaths due to treatment toxicity were observed, and no severe infections, liver failure, or lung fibrosis. More brain edema was observed in the combination arm, and more low-grade alopecia (patchy hair loss).

The authors concluded by noting that acute toxicity of the combination treatment was rare, and importantly, "the primary aim of CeTeG/NOA-09 was achieved: the OS superiority of CCNU/TMZ for MGMT promoter methylated newly diagnosed GBM could be demonstrated".

This may well be the most significant trial outcome reported at the 2017 SNO conference. Since TMZ was approved for newly diagnosed glioblastoma in 2005, it has been exceedingly rare for a phase 3 trial in the newly diagnosed GBM setting to achieve statistically significant prolongation of survival with a novel regimen.  More work needs to be done to explain why progression-free survival benefit was more modest than overall survival benefit in this trial. A potential hypothesis for the improved survival results for the combination therapy is a possible synergistic interaction between TMZ and CCNU, whereby cells escaping sensitivity to TMZ through mismatch repair defects are thereby rendered more sensitive to the CCNU treatment (Stritzelberger et al. 2017). Now that the results of CeTeG have been reported to the international neuro-oncology community, the mechanisms behind the improved outcomes with the combination chemotherapy will likely become the subject of more intense investigation.

BGB-290 (brain penentrant PARP inhibitor) trial now open in USA

Formerly this drug was only available in 2 Australian clinical trials.  A trial has now opened in the USA (Arizona, Colorado, Tennessee, not yet open in Oklahoma) for newly diagnosed GBM with unmethylated MGMT, or for recurrent GBM (methylated/unmethylated MGMT), combined with standard treatments (temozolomide + BGB-290 in the recurrent group).

https://clinicaltrials.gov/ct2/show/NCT03150862

Past post that mentioned BGB-290 and PARP inhibitors.
http://btcocktails.blogspot.com/2017/07/parp-combination-therapy.html

PARP combination therapy

Hello all,

I came across this article:

PARP inhibitor combination therapy

"Here, we summarise both the pre-clinical and clinical evidence for the utility of such combinations and discuss the future prospects and challenges for PARP inhibitor combinatorial therapies."
http://dx.doi.org/10.1016/j.critrevonc.2016.10.010

Does someone have experience regarding PARP combination therapy? I know this has been discussed before in other posts especially when a tumour is IDH1-mutated. In the article they also propose that MGMT methylation is positive factor for PARP therapy.

It would be interesting to see results from trials or hear personal experiences on PARP therapy.

All the best,
Juha

PARP Inhibitors - Combining SAHA and Olaparib? Preparing for plan b

Hi All,

My Dad was diagnosed with a GBM in October 2016 and has since had chemoradiation, on his 5th TMZ cycle, and has had two Avastin infusions.

The Avastin infusions immediately cleared up his MRIs (the inflammation, not the tumor) and have allowed us to taper his decadron from 4mg/day to 2.5mg/day, but we know that Avastin is not the long term answer so I am preparing for our next step.

As I'm sure everyone is, I'm pushing to have a better than standard of care "newly diagnosed stage" plan (which is right now), as well as a plan for if/when we hit the "recurrent stage".

My last post mentioned our NO's interest in Abemaciclib and the possibility of getting compassionate use, but since then our NO was at a Brain Tumor Conference in Zurich, Switzerland (Lilly, the drug manufacturer of Abemaciclib was there) and did not receive any promising results or information to keep us pursuing this path.

Our next plan is to look at PARP Inhibitors. An article and strategy that quickly caught my families attention is about the combination of SAHA (an HDAC class I + II inhibitor) and Olaparib (a PARP inhibitor).

See the following article below:
https://www.ncbi.nlm.nih.gov/pubmed/26794465

and for full article see this link:
http://onlinelibrary.wiley.com/doi/10.1016/j.molonc.2015.12.014/full

A previous post on this blog mentioned Rucaparib (another PARP inhibitor) has been shown to not penetrate the blood brain barrier effectively, but has anyone heard specific results about oliparib?

Both Olaparib and SAHA are being tested individually in currently active clinical trials with TMZ but I have not been able to find any of the results.

One caution our NO mentioned was that PARP inhibitors can cause issues with blood counts, especially for someone who is on TMZ cycles.

Would love to hear what you all think about this plan and whether you have heard the good/bad/ugly on the PARP Inhibitor trials I mentioned about.

Amazing community we have here. Thank you all for the time.

Ari
Oakland, CA

Oligo 2 meeting with Patrick Wen

Hello,

I met with my NO Dr. Patrick Wen who is director of Dana Farber NO department yesterday. While I 'm stilling awaiting surgery, and therefore pathology, Dr. Wen feels my tumour is most likely an Oligo 2. It is 3cm in left left frontal lobe. I'm 35.

Dr. Wen told me most of these will recur around 10 years (for this location, size, my age, and depending on resection, etc). He also said he believes it's not unrealistic to think that by then there'll be an effective therapy to stop IDH mutant tumours from growing, essentially turning it into a chronic condition. He has a low grade patient (or more) who he was meeting with before me who has been on and IDH inhibitor for a year and a half now. Those seemed to be most promising to him.  He also mentioned PARP inhibitors and a number of other promising agents. He named about 6, including demethylating agents which seemed like a new idea.

I thought I'd share, because it was really helpful to me. He is very optimistic. He said that all of NO is focused on this mutation right now.


I know that's not useful to others without the mutation. Sorry.


I also thought I'd share his video addressing the recent WHO reclassification of these tumours. Most people on here  probably know this but on other blogs it seems a lot of people do not. Their type of tumour may have been essentially misdiagnosed all along.

http://www.practiceupdate.com/content/new-classification-scheme-for-low-grade-gliomas-clinical-implications/33428

It's my understanding that there is no longer a grey area. You must have co-deletions and IDH mutation to have an Oligo. Without the co-deletions it's an Astrocytoma and without IDH mutation it's a glioblastoma. I often see things that read "80% of Oligos have co-deletions (or IDH mutation)" but you can no longer be diagnosed with an Oligo if it doesn't have these characteristics. Grading is then related to not yet malignant (low grade) or malignant (high grade). I also believe they can lose their co-deletions, progressing to and Astrocytoma but are not likely to lose the IDH mutation. Maybe Stephen, or others, will be gracious enough to let me know if I have this correct.

I'm curious to know how likely Pligos are to lose their co-deletions upon first recurrence. I'm not sure this information is available.


Maria

Olaparib

Hello guys,

2 days ago a study about olaparib and IDH mutant gliomas appeared. Since olaparib is already an approved PARP inhibitor for treatment of ovarian cancer and trial for gliomas in the end of 2017 is expected, I thought someone might find it useful.

"The researchers tested several existing cancer drugs on the mutated cell lines. They found that tumor cells with the mutant genes were particularly sensitive to a drug, olaparib, recently approved for the treatment of hereditary ovarian cancer. The drug caused a 50-fold increase in brain tumor cell death."

https://www.sciencedaily.com/releases/2017/02/170202141211.htm

And link to the study:

2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity

http://stm.sciencemag.org/content/9/375/eaal2463 

Also I did a quick search for olaparib and glioma and there are already trials with olaparib and TMZ for recurrent GBM.