AACR 2019 – Rubraca trial points to a place for Parps in pancreatic cancer

Encouraging early data from an academic trial of Clovis's Rubraca raise hopes that Parps could emerge as a more tolerable maintenance therapy for some pancreatic cancer patients. 

Impressive results from a small trial of Clovis’s Rubraca as a maintenance therapy in pancreatic cancer patients point to what Parp inhibitors might be capable of in this setting. Since this setting is currently the realm of highly toxic platinum-based chemotherapies, the prospect of a more tolerable treatment regimen, for certain patients at least, represents a notable advance in an area more commonly associated with setbacks. 

At AACR today investigators from Penn University reported results from an uncontrolled trial recruiting patients positive for BRCA or PALB2 genetic mutations, who were in response to first-line chemotherapy. Six-month progression-free survival in such subjects approximates to 44%, the researchers said, and the trial aimed to push this above 60%.

The six-month PFS in the study currently stands at around 70%, the AACR data revealed. An overall remission rate of 38% has been achieved in the 19 patients evaluable so far, comprising one complete and six partial responses. Median PFS, from the start of Rubraca dosing, is 9.1 months, while median overall survival has yet to be reached.

Penn's Dr Kim Binder, presenting the data at an AACR press conference this morning, said the main goal of this trial was to maintain efficacy but cut chemo-associated toxicity, since demonstrating increased survival would necessitate a controlled study. "If we can improve on efficacy that would be great," she added.

She touted the results as highly encouraging, stressing no reported dose-limiting toxicities, but also cautioned that this was far from the final analysis of the trial, which seeks to recruit 42 subjects in total.

Polo success

These findings make for very interesting reading in the wake of Astrazeneca’s success with the phase III Polo study of its Parp inhibitor Lynparza in a very similar setting; earlier this year the company said the trial had met its primary PFS endpoint, and a look at the data is keenly awaited. When this might be has yet to be disclosed, though Asco seems a likely venue. 

The Penn study of Rubraca recruited similar patients to Polo, though it is not immediately clear whether Polo also selected for the PALB2 genetic mutation, which occurs even less frequently than BRCA. 

Around 6-8% of pancreatic cancer cases harbour either BRCA or PALB2 mutations, according to the Penn researchers. These tumours frequently respond very well to platinum-based chemotherapies, but long-term maintenance therapy is marked by substantial toxicities, hence the hope that the Parp class might offer a more tolerable option.

Selected trials of Parp inhibitors in pancreatic cancer
Trial name/ID Setting/description  Product  Sponsors Enrolment Primary completion
Phase III
Polo (NCT02184195) BRCA +ve, maintenance Lynparza Astrazeneca/Merck  154 Primary endpoint met, awaiting full data
Phase II
NCT03140670 BRCA/PALB2 +ve, maintenance Rubraca  U. Penn 42 Interim reported, primary completion 30/06/2021
NCT02890355 All comers, second-line, metastatic Veliparib plus FOLFIRI or modified FOLFIRI. NCI 143 May 2019
Parpvax (NCT03404960) All-comers, maintenance  Zejula + Yervoy or Opdivo U. Penn 84 Jan 2021
NIRA-PANC (NCT03553004) DNA repair mutation, second-line, metastatic  Zejula U. Kansas  18 Feb 2021
NCT03682289 Basket trial incl pancreatic settings AZD6738 +/- Lynparza U. California 68 Mar 2021
NCT03601923 DNA repair mutation, second-line, metastatic Zejula Dana-Farber  32 Feb 2022
Dapper (NCT03851614) Basket trial incl pancreatic setting Imfinzi + Lynparza or Imfinzi plus cediranib UHN, Toronto 90 Mar 2022
Source: EvaluatePharma, clinicaltrials.gov.

Considering the strong scientific rationale for treating patients with a BRCA or related genetic mutation with a Parp inhibitor, it is notable that industry has invested little effort in testing these agents in pancreatic cancer. This is probably down to the historically intractable nature of this disease, and the relatively small commercial opportunity, but as the table above shows there has been a fair amount of academic interest. 

Trials of note here include a study called Parpvax, which is also being run at the University of Pennsylvania. This is looking at whether checkpoint blockade can add anything to Parp inhibition in patients who respond to platinum chemotherapies; all patients regardless of genetic mutations are being recruited, presumably to see if the scope of the Parp inhibitors can be broadened to other types of homologous recombination deficiencies, of which BRCA is one example. 

In terms of commercial advantage, Astrazeneca and Merck & Co with Lynparza are obviously ahead here, but the trial reported today also stands Clovis in good stead. After Tesaro was bought by Glaxosmithkline Rubraca is the only Parp inhibitor in the hands of a small company, and Clovis needs all the help it can get.

This is an updated version of an earlier story.

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