Combination of camonsertib plus PARPi shows clinical activity in DDR-aberrant tumours

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Published: 25 Apr 2023
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Dr Timothy Yap - The University of Texas MD Anderson Cancer Center, Houston, USA

Dr Timothy Yap speaks to ecancer about the safety and efficacy of three PARP inhibitors combined with the ataxia telangiectasia- and Rad3-related kinase inhibitor camonsertib, in patients with solid tumours harbouring DNA damage response alterations.

The study explored patients (≥ 18 yrs) with relapsed/refractory solid tumours with DDR alterations which were treated with camonsertib plus talazoparib, niraparib, or olaparib in 2 phase I trials.

The combination of camonsertib plus PARPi at low doses on intermittent schedules was generally well-tolerated with clinical activity in DDR-aberrant tumours, including those pretreated with PARPi. Dr Yap continues to discuss the results of the study.

I presented data on the safety and efficacy of three different PARP inhibitors combined with the ATR inhibitor camonsertib in patients with advanced solid tumours harbouring DDR or DNA damage response alterations. The whole rationale for this combination is really to improve on the efficacy of monotherapy PARP inhibitors. We now have four different PARP inhibitors that are approved by the FDA for use in different indications. However, the main issues are resistance – whether that is primary resistance or secondary resistance. But that eventually, inevitably, leads to disease progression and therefore there’s a real clinical unmet need to do better for our patients and to improve on the efficacy for our patients.

The main issue that we have is that when we combine PARP inhibitors with specific other agents like chemotherapy or other agents there is often overlapping toxicity which makes it very hard to develop a wide enough therapeutic window. Particularly when you combine a PARP inhibitor with an ATR inhibitor which is a very rational approach to try and improve on the efficacy, we do see overlapping toxicity. What occurs is that ATR inhibition prevents the recovery from PARP inhibitor induced DNA damage by a rapid irreversible replication catastrophe and unscheduled mitosis entry, eventually leading to cell death. Therefore the combination of a PARP inhibitor and an ATR inhibitor really does provide a rational approach to improve PARP inhibitor efficacy and we have observed robust pre-clinical PARP inhibitor and ATR inhibitor synergy in models harbouring homologous recombination deficiency phenotypes including BRCA1, BRCA2, ATM and CDK12 alterations. This combination has been shown to delay or to overcome acquired PARP inhibitor resistance.

Importantly, when trying to optimise the dose and the schedule of this particular combination we showed that intermittent low dose of camonsertib and PARP inhibitors was active in preclinical models. Particularly a three days on, four days off, weekly schedule of low dose camonsertib and olaparib showed sustained tumour growth inhibition compared to single agent. An intermittent concomitant schedule was also well tolerated in mice with no bodyweight loss and it also showed more sustained efficacy versus sequential administration. 

Importantly, the efficacy with these intermittent schedules was similar between different PARP inhibitors and, based on these promising preclinical data, we then proceeded to clinical trials testing camonsertib with three different PARP inhibitors, including olaparib, talazoparib and niraparib. What we found with these combinations in the clinic was that this particular dosing schedule of low dose intermittent regimens of camonsertib with these three different PARP inhibitors was safe with only transient haematological events. Most patients’ counts actually rebounded within a week of drug hold if necessary and, importantly, no prophylactic growth factors were required. 

Significantly, anti-tumour activity was observed in patients with platinum and PARP inhibitor resistant tumours with pre-defined genomic alterations. The anti-tumour activity was encouraging and very durable with a clinical benefit rate of 48% out of 90 patients. Patients with late line ovarian cancer derived the most benefit from therapy with an overall response of 32%, a clinical benefit rate of 58% and a median progression-free survival of seven months which compares favourably to current therapeutic options for these patients. The molecular response rate was 66% in 47 evaluable patients, really supporting the anti-tumour activity of these combinations.

Dose optimisation to refine a tailored combinatorial dose and tumour-specific expansions is currently ongoing and this approach could represent a novel strategy in areas of unmet clinical need.