Major Breakthrough in the Treatment of Triple Negative Breast Cancer
- A recent updated analysis of the original BS-201 PARP Inhibitor (PARPi) Trial continues to show an exceptional outcome benefit to the addition of the PARP inhibitor (PARPi) BSI-201 to the gemcitabine-carboplatin chemotherapy backbone, and although these are interim and not final results which could change in either direction, at this time the interim findings support the provisional conclusion that the PARP inhibitor essentially - and amazingly - doubles overall survival (OS) - not just PFS (progression-free survival), also improved, meaning reduction in the risk of recurrence - in the triple negative breast cancer population, and at this time sustains a 50% reduction in the risk of death.
[Disclaimer: we must wait the final results of the trial to see if these dramatic, first-ever results, are sustained at the same or reasonably comparable levels as now seen with the interim findings].
- These rather stunning survival outcomes were furthermore accompanied by highly impressive response rates: the overall response rate (ORR) was high, at 48% of patients achieving complete response (CR) or partial response (PR) which is three times as high as that obtained with chemotherapy alone, and with another 14% achieving stable disease (SD, for 6 month or greater), yielding a clinical benefit rate (CBR) of 62% (CBR = CR + PR + SD), and with no significant additional adverse effects from the addition of BSI-201 to the chemotherapy backbone (impressive, remembering that non-toxic agents are notoriously hard to come by in oncology).
- The accrual and progress of the trial has proceeded at extremely rapid pace, well beyond expectations, and the best estimation, based on feedback from investigators, is that this Phase III trial given the pace, will come to completion as early as this (First) Quarter of 2010. Interview statements - but not officially posted NCI protocol data - suggests that there are just 40 patients remaining requiring trial accounting, 20 in the PARP inhibitor arm, and another 20 in the chemotherapy only arm, confirming that completion is very close, and that a First Quarter 2010 estimate is plausible on the progress to date.
- Finally, on the regulatory front it also appears there is accelerated progress: the PARP inhibitor BSI-201 has been granted on Fast Track Designation by the FDA, very good news for patients: FDA Fast Track means that, against standard requirements, the agency will accept initial late-stage data instead of waiting for entire Phase III clinical trial results, something that is done when (1) a proposed agent is intended for treatment of a serious or life-threatening disease - a status now accepted by the FDA for mTNBC (metastatic TNBC) - and (2) demonstrates the potential to address unmet needs for such a condition. Based on this status and on a review of documents filed in the FDA regulatory pipeline process, it is now estimated that BSI-201 may actually become commercially available - and hence available to all mTNBC patients in clinical practice without being on any clinical trial - at year's end (mid November to mid December, best estimate).
Commentary: Missed, and New, Opportunities
My own sense of the ASCO BSI-201 PARP trial is that on the contrary that it may have underestimated the true benefit; this perspective stems from my own TNBC review and research which on the cumulative evidence suggests that maximal benefit of PARP inhibition is accrued when it is concurrent with a strongly genotoxic (DNA-damaging) regimen, and although carboplatin is genotoxic, as are all platinum agents, gemcitabine (Gemzar) is not, and I believe this represents a lost opportunity. Indeed, I have on several occasions advocated in this context the omission of gemcitabine (Gemzar) altogether in the PARP context, in favor either of (1) a more optimal dose of carboplatin - I consider carboplatin AUC=2 as substantially sub-optimal, and would have deployed at least AUC=6 even up to AUC=7.5, or (2) substituting another genotoxic agent instead of gemcitabine (Gemzar), my choice being an anthracycline (preferably the pegylated liposomal Doxil or Caelyx. Given this limitation - which in all fairness the principal investigator Joyce O'Shaughnessy has acknowledged (due to expediency, not oversight) - of the failure to maximize the potential synergy of genotoxicity and PARP inhibition, in my mind therefore the trial's findings are actually therefore even more impressive by extrapolation, ad I would predict that an all-genotoxic chemotherapy + PARP inhibitor (BSI-201) will achieve significantly greater outcome benefit than even doubling of survival and halving of mortality for metastatic TNBC patients.
And this is where the opportunity can be regained, in the earlier availability of BSI-201 by this year's end, since at that point clinicians are no longer constrained to conform to the trial protocol's chemotherapy regimen, and I would advocated for them to instead adopt a more optimal all-genotoxic regimen which should translate to even more dramatic outcome gains. I am also of the opinion for molecular and other reasons that the failure of response of the PARP inhibitor regimen for some patients may be due in part to the absence of pure genotoxicity in the combination regimen, which therefore I am hoping innovative oncologists will recognize and overcome through appropriate DNA-damaging agent substitutions for the non-genotoxic gemcitabine (Gemzar) component, allowing more patients to be responsive to this breakthrough for metastatic TNBC disease.
Come The Revolution
Finally, remember the last time we heard of a 50% gain in breast cancer survival? That was with the revolutionary, practice-changing (virtually overnight) findings from Dennis Slamon's trial on trastuzumab (Herceptin) for HER2-positive disease, heralded correctly as the greatest breakthrough in breast cancer treatment since tamoxifen 30+ years ago. I believe an optimally genotoxic PARP inhibitor therapy can do for triple negative disease what Herceptin did for HER2+ patients, and the provisional results of the Phase III PARP Inhibitor to date appear to support and imply that contention.
These are the kind of times that researchers like me - and dedicated and brilliant investigators, and soon also patients - live to see as their reward for their commitment.