BRCA1, BRCA2 or PALB2 in pancreatic cancer.


This study that we presented at ASCO is titled a descriptive study on the treatment and outcomes of patients with platinum sensitive advanced BRCA or PALB2 related pancreatic cancers who have progressed on recappery so basically what this study was is a follow-up study to a phase two clinical trial of patients with platinum sensitive advanced pancreatic cancer who had a germline or somatic pathogenic variant in BRCA1, BRCA2 or PALB2 patients who had who had platinum sensitive disease where were placed on a maintenance recap rib treatment which is a parp inhibitor the clinical question we had was how do we treat these patients after their cancer has progressed on recap and pancrease cancer in particular is very limited data to guide our our management so broadly what we were interested in is looking at what patients were treated with after they 've after they 've come off the protocol study and broadly we were interested in particular in the use of platinum-based versus non-platinum-based chemotherapies we looked at outcomes such as overall survival progression-free survival objective response race by racist 1.1 and an endpoint called pfs2 which we defined as the time frame enrollment on the initial clinical trial until progression on the second line chemotherapy the original clinical trial had 42 patients that had enrolled of these 42 18 had progressed and were treated with platinum-based chemotherapy five progressed and were treated with non-platinum-based chemotherapy 11 patients at the time of data cut off remained on the initial clinical trial six patients did not receive any further therapy after progression and two patients received other therapies such as targeted therapies or radiation broadly what we found was that of the 18 patients who received platinum-based chemotherapy after progression on recapperib the median overall survival was 14.8 months of those of the five patients who received non-platinum-based chemotherapies the median overall survival was 28.9 months although there 's a numerical difference here the limited sample size prevent us from drawing any definitive conclusions about superiority the objective response rates for those who receive platinum-based chemotherapies was 22.2 percent whereas those who received non-platinum-based chemotherapies was 40 percent we also looked at the type of platinum that uh patients that patients received if they received further platinum-based chemotherapy there were nine patients who received a cisplatin-based regimen and nine patients who received an oxalic platinum-based regimen the patients who received cisplatin had immediate overall survival of 13.8 months and those who received oxalate platinum-based therapies had a median overall survival of 19 months the objective response rates for those who received cis platinum was 11.1 compared to 33.3 percent for those who received oxaliplatin we could not identify any particular patterns with regard to times that patients spend on recappyrib and and outcomes following following progression on chemotherapy and so the conclusion from this uh study was that this is a a small observational study where we looked at how to treat patients following progression on chemotherapy and although the sample size is too small to make any definitive comparisons it does appear that chemotherapy still remain an option in select patients.

Question - Common Questions From Your Colleagues?


So, I think the most common clinical question that clinicians have after treating patients with pancreas cancer on parp inhibitor is can you still use platinum-based chemotherapies because we believe that if patients have progressive disease on platinum-based chemotherapies parp inhibitors won 't work we don 't necessarily know that the alternative is true if patients who progress on parp inhibitors if we can still use platinum-based chemotherapies it does appear based off the results of this study that platinum-based chemotherapy still have some activity in this patient population.


Question - Will This Affect Clinicians In The Future?


So, we are still hoping to better define how to identify which patients should be treated with platinum-based versus non-platinum-based chemotherapy as the subject of ongoing work I would say today and in the future clinicians can feel comfortable tailoring post-progression chemotherapy decisions based off of patients ' individual.


Question - What Are The Next Steps?


Comorbidities so currently we are attempting to better understand the uh the genotype-phenotype connection between BRCA and PALB2 mutations as well as their response to both park inhibitor therapy and post-progression chemotherapy this is work that is ongoing that we 're hoping to finish in the next year or so.


Question - Final Thoughts


So, again I want to emphasize that patients who have progressive disease on parp inhibitor they can still be treated with chemotherapy if they are still treatment candidates I think that we still have too small of a sample size to derive any definitive conclusions between which chemotherapy regimens are the uh the most effective or quote-unquote the best for patients but this is reassuring that there is still activity for these for these patients.


Timothy Brown, MD, Chief Fellow at the Abramson Cancer Center, Hospital of the University of Pennsylvania. In this video, he speaks about the ASCO 2022 Abstract - A descriptive study on the treatment and outcomes of patients with platinum-sensitive, advanced, BRCA- or PALB2-related pancreatic cancer who have progressed on rucaparib.


The results of a single arm phase II research of rucaparib maintenance in patients with platinum-sensitive advanced pancreatic cancer and a pathogenic mutation in BRCA1, BRCA2, or PALB2 were recently published (NCT03140670; Reiss, JCO 2021). However, the best treatment after advancement on PARP inhibitors (PARPi) has yet to be determined. We present a descriptive study of this patient population 's 


Patients with advanced pancreatic cancer and germline or somatic BRCA1, BRCA2, or PALB2 mutations who had not progressed after at least 16 weeks of platinum-based chemotherapy were enrolled and given rucaparib until progression or intolerable toxicity. Patients were treated with chemotherapy of their choice at the time of progression. RECIST 1.1 is used to assess objective response rates (ORR). Secondary objectives included overall survival (OS), time to second progression (PFS2) determined from study enrolment, and progression free survival on chemotherapy (PFS) by regimen. The Kaplan-Meier approach was used to calculate time-to-event, which was censored at the date of the previous clinic visit, with a cutoff date of 12/10/21.


The trial enrolled 42 patients, with 31 of them progressing. Of them, 22 got second-line chemotherapy, with nine receiving an oxaliplatin-based treatment, nine receiving a cisplatin-based regimen, and four receiving non-platinum regimens. Demographics were balanced between those who received platinum and those who did not. All patients who underwent second-line treatment met the PFS2 endpoint, and all but one had died by the time the data was shut off. There were no complete responses, and five patients had partial responses (PR). By regimen, 1/9 of cisplatin patients had a PR, 3/9 of oxaliplatin patients had a PR, and 1/4 of non-platinum patients had a PR. The table displays the OS, PFS2, PFS, and ORR data by regimen.


Chemotherapy retains some activity in this small sample of patients with advanced pancreatic cancer and progressing illness on PARPi. More research is being conducted to discover determinants of response and/or resistance to post-PARPi treatment.