One of the most noticeable things about this year's annual meeting is how many of the pathways that were being discussed at AACR research in recent years are now producing early data in the clinic. One such pathway is PARP, where two oral abstracts were presented today.
In the plenary session, Dr Joyce O'Shaughnessy presented the phase II data for BiPar and sanofi-aventis' PARP inhibitor, BSI-201. This was preceeded, however, by a most entertaining presentation on the pathway by Dr Merrill Egorin from Pittsburgh. Through his exceelntly distilled synopsis we learned that PARP is a key regulator of DNA damage and repair processes, including DNA base excision repairs. More detailed inofrmation can be found in two technical papers published in Nature by Drs Farmer and Bryant, both in 2005.
Dr O'Shaughnessy described tumours as essentially a situation in which cancer cells have lost the ability to repair damaged DNA. In this study, data was presented in triple negative breast cancer (TNBC), which has a typically poorer prognosis compared with other subsets of breast cancer. Patients were randomised 1:1 to receive either a chemothrapy doublet (gemcitabine plus carboplatin) or chemotherapy plus BSI-201.
The primary endpoints were clinical benefit rate and PFS. Secondary endpoints included overall survival, although this data will not be available until fourth quarter of 2009.
Results reported in the patients so far were as follows:
Gem/Carbo Gem/Carbo + BSI-201
ORR 16% 48%
CBR 21% 62%
PFS 3.3 mon 6.9 mon
OS 5.7 mon 9.2 mon
There were no differences in non-hematologic toxicities and grade 3/4 were uncommon to date.
The authors concluded that PARP1 is upregulated in most TNBC's, BSI-201 was well tolerated and patients showed significant clinical outcomes. On the basis of these results, a phase III trial is being established and is expected to be open in late June.
A second phase II trial looking at PARP inhibition was presented by Dr Tutt et al. They examined the effect of olaparib (AZD2281) from AstraZeneca and KuDOS in BRCA1 and BCRA2 breast cancer. This study looked at refractory disease where patients had previous received chemotherapy such as an anthracycline and a taxane. They compared the impact of two different doses of olaparib orally, i.e. 400mg BID and 100 mg BID, on overall response rate and complete/partial responses.
The results were as follows:
400 mg BID 100 mg BID
ORR 41% 22%
CR 4% 0%
PR 37% 22%
PFS 5.7 mon 3.8 mon
However, the combination was not without toxicities, with grade 3 adverse events occurring more frequently in the higher dose arm, and the most common (grade 3 or more) being fatigue (15%) and nausea (19%).
The authors of this trial concluded that it was the first report for a therapy designed for BCRA1/2 in breast cancer patients. Single agent activity in the 400mg arm was substantial compared to the 100mg arm and the treatment was well tolerated.
There are few options in BRCA positive disease – it occurs in both breast and ovarian cancers – so AstraZeneca may try seek an accelerated approval for this agent. It will be interesting to see sanofi-aventis and AZ battle it out for the honour of the first PARP inhibitor approved in breast cancer. Watch this space!