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BY DEBU TRIPATHY | APRIL 8, 2011
The Feb. 28 posting regarding PARP inhibitors drew several comments I thought should be addressed. There has been considerable interest in PARP inhibitors because of the early activity cancers associated with BRCA1 and BRCA2 mutations, as well as triple-negative (estrogen, progesterone and HER2 receptor-negative) breast cancer.
The fact that the follow-up and more definitive phase 3 trial comparing chemotherapy with or without the PARP inhibitor iniparib (also known as BSI-201) did not confirm the dramatic survival benefits seen in the earlier and smaller phase 2 trial raised a lot of questions.
Our readers have responded with queries and some degree of dismay, including those who are currently on the expanded access trial with this drug. The evolution of descriptors from "spectacular" to "exciting" to "not meeting its endpoint" is a repeated theme in science as we go from preliminary data, where conclusions are shakier (but tantalizing because they are new) to more definitive studies, where the results are more reliable, but may not always confirm the earlier findings.
However, there are some details in this particular case that are worth mentioning, some of which were alluded to in comments from our readers. The phase 2 and 3 trials had equivalent treatment arms, but the endpoints were not the same. The phase 2 trial was initially designed to see if cancer could be stabilized in more patients receiving iniparib added to chemotherapy compared with chemo alone. There was an unexpected improvement in survival with the addition of iniparib - greater than has been seen with any other drug. This led to the phase 3 trial being designed with very high expectations – that both survival and disease-free survival would be improved. Therefore, both these endpoints were built into the statistical analysis plan. When the result fell short of the "p-value," or the level of statistical significance, the trial was declared to have not met its endpoint. However, it is important to note that there still could be an important benefit for all patients. Just not by the definition set for this trial, which was expected to win FDA approval.
It is also possible that patients receiving first-line therapy were not the same as those receiving second or third line therapy, since those who have very aggressive cancer initially might not qualify for later lines of therapy. This type of selection bias could result in a different biological profile such that PARP inhibitors might work better in those who are able to make it to second/third line treatment, as was demonstrated in the Phase III trial.
Of course, these are all speculative reasons for these results, and only diligent completion of the planned trials will ultimately answer these questions. In the meantime, we should recognize the elegance of targeting DNA repair, and those who are on clinical trials with PARP inhibitor should certainly continue, with the same hope that this drug can make a difference.
The truth will eventually emerge, and while it is possible that we might be disappointed, the data so far suggests that PARP inhibitors will be effective drugs – it remains to be seen which inhibitor (since they all seem to be different) and which patients will benefit (since we don't know which tumors really rely on this enzyme).
Science is not only about cold facts – it involves drama, emotions and contradictions. But ultimately, truth prevails with well-designed studies and patients – just not as soon as we would like.
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I was diagnosed with Triple Negative Cancer in Feb 2009 and was told there was no treatment just chemo and radiation hope it worked. Then I read about PARP drugs and wanted to be in on their experimental use (didn't happen). On Oct 5, 2010, I was diagnosed with a liver mets (Stage IV) and it is the same type of cells from the 2009 cancer. I am told noe the PARP drugs didn't have good reactions in the research field. Once again chemo is the answer,I took Carboplatin and Ixabepaproplone until my quality of life was nil and I was literally dying from the drugs- I was in a research program. Stopped the chemo for three weeks and the tumors grew and got three more; now I am on Doxil every 28 days. I know chemo is to be done for the rest of my life, but I am still interested in the PARP drugs or any other drugs available for TNBC. I read CURE to see what is available and my oncologist is looking for new drugs. After two more Doxil treatments, I will go to a third line drug which has recently approved by FDA. Keep me informed for ANY drugs available to treat this very agressive cancer; No one should have to face the diagnosis of TNBC and find out there is no treatment to keep it in check (I know there is never a cure, just remission and mine lasted 15 months). Thanks for all you all do for cancer and finding "cures".
- Posted by Betty Parton 4/21/11 5:21 AM
I was diagnosed with Er+Pr positive breast cancer. I had mastectomy. After surgery, I had chemo Iv and pill form.After almost 3 years, cancer reappeared and spreaded to Lungs as small dots. A second line of chemo started but did not do good. Dr. gave 3rd. line of chemo from the established list of chemo treatment. But this tough cancer did not yield and spreaded to spine bone at T1. Radiation treatment did not work to reduce the size or stablize it. Almost 2 years passed, a chemo drug known as Ixempra was given every three weeks. The results are not known whether it is working but all these chemo treatments worked on body and mind to become weak. A problem I see on the very first time after bisopsy whether Dr. had asked treatment center to find out which drug will be effective based on the analysis of tumor sample. I thought that this would have been a standard procedure established by Oncologists Association or Hospital where biopsy was done. What do you know about this. i would like to know. I undertand when I contacted cancer research organization. They told me that this would be a standard procedure. i am wondering Why this was not done in my case. I am suffering all lot from all sides. So far I had these chemo drugs in order. Andriamycin+ Cytoxan + Dexamethosone before surgery; 5-FU + Methotrexate(IV) + Cytoxan tab post surgery : Arimidex tab stopped until relapse. ; Taxol + Carboplatin after relapse : Armasin tab; Bavelbine chemo ; 5-FU continous infusion; now Ixempra will see results. Please let me know what would be the next in line. Yhanks
- Posted by Sumati SHah 4/21/11 2:00 PM