Targeting DNA Repair in Metastatic Pancreatic and Prostate Cancers

PARP inhibitors benefit observed beyond treatment for breast and ovarian cancers

There is a dozen of currently approved indications for PARP inhibitors for the treatment of breast and ovarian cancers and the results from additional studies shifting to front-line management are awaited. The studies presented at 2019 ASCO Annual Meeting further expand PARP inhibitors portfolio. In particular, POLO is the first phase III trial to validate a biomarker-driven treatment in metastatic pancreatic cancer. Among patients with a germline BRCA mutation, progression-free survival (PFS) was longer with maintenance olaparib than with placebo following first-line platinum-based chemotherapy. TOPARP-B, a phase II randomised trial of olaparib for metastatic castration resistant prostate cancers (mCRPC) with DNA damage repair (DDR) alterations showed that olaparib has antitumor activity in heavily pre-treated patients with DDR gene defects, with BRCA1/2 aberrant tumours being most sensitive, but with confirmed responses in patients with other DDR alterations recorded as well. The results from TOPARP open the hints in this setting as the results from the phase III clinical trial are awaited.

Phase III POLO trial

Hedy Kindler of the University of Chicago reported the results on behalf of POLO investigators at 2019 ASCO Annual Meeting. The findings were simultaneously published in The New England Journal of Medicine. She said that patients with a germline BRCA1/2 mutation are a small subgroup (4-7%) of those with metastatic pancreatic cancer. Kaufman et al. showed in 2015 that olaparib has antitumour activity in this population. POLO is the first phase III trial to evaluate efficacy of maintenance treatment with a PARP inhibitor in pancreatic cancer.

The POLO investigators conducted a randomised, double-blind, placebo-controlled, phase III study to evaluate the efficacy of olaparib as maintenance therapy in patients who had a germline BRCA1/2 mutation and metastatic pancreatic cancer and disease that had not progressed during first-line platinum-based chemotherapy. Patients were randomly assigned, in a 3:2 ratio, to receive maintenance olaparib tablets (300 mg twice daily) or placebo. Median age of patients was 57 years and ECOG performance status was predominantly 0.

The study primary endpoint was PFS that was assessed by blinded independent central review.

Of the 3315 patients who underwent screening, 154 underwent randomisation and were assigned to a trial, in particular 92 to receive olaparib and 62 to receive placebo.

The median PFS was significantly longer in the olaparib group than in the placebo group (7.4 months vs. 3.8 months (HR 0.53; p = 0.004) and consistent irrespective of response to prior platinum-based chemotherapy (complete/partial HR 0.62; stable disease HR 0.50). From 6 month, the percentage of patients progression-free in the olaparib arm was more than twice than in the placebo arm.

An interim analysis of overall survival (OS), at a data maturity of 46%, showed no difference between the olaparib and placebo groups; median, 18.9 months vs. 18.1 months. Final OS results will be evaluated at 69% data maturity.

There was no significant difference in two groups in health-related quality of life (QoL) based on the EORTC QoL Questionnaire. The incidence of grade 3 or higher adverse events was 40% in the olaparib group and 23% in the placebo group; 5% and 2% of the patients, respectively, discontinued the trial intervention because of an adverse event.

The authors concluded that maintenance olaparib provided a statistically significant and clinically meaningful improvement in PFS in patients with metastatic pancreatic cancer and germline BRCA mutation who had not progressed on first-line platinum-based chemotherapy. Safety was consistent with the known profile for olaparib. These results are the first from a phase III trial to validate a targeted treatment in a biomarker-selected population of pancreatic cancer patients, highlighting the importance of germline BRCA mutation testing in this setting.

The POLO study was funded by AstraZeneca and others.

Wells Messersmith of the University of Colorado Cancer Center entitled his discussant talk ‘Pancreatic Cancer Gets Personal’. Genetic alterations in pancreatic cancer according to The Cancer Genome Atlas show complex molecular landscape with ‘top 4’ mutated genes being KRAS, TP53, CDKN2A, SMAD4 and predicted pathogenic germline mutations in 8% of patients (BRCA2, ATM, PALB2, BRCA1 and others). According ‘Know Your Tumor’ programme among 640 patients from 287 academic and community practices from whom 458 had metastatic disease, 15% had alterations in DNA repair.

He also touched NCCN Updated Guidelines 2019, in particular pancreatic cancer guidelines released on 9 April 2019 which states that germline testing is recommended for any patient with confirmed pancreatic cancer using comprehensive gene panels for hereditary cancer syndromes. Genetic counselling is recommended for patients who test positive for a pathogenic mutation or for patients with a positive family of cancer. Tumour/somatic gene profiling is recommended for patients with locally advanced/metastatic disease who are candidates for anticancer therapy, to identify uncommon but actionable mutations. NCCN Genetic/Familial High Risk Assessment: Breast and Ovarian, guidelines version dated of 18 January 2019 states that genetic risk evaluation is recommended for any individual diagnosed with pancreatic cancer.

Phase II TOPARP-B study

Joaquin Mateo of The Institute of Cancer Research & The Royal Marsden, London, UK and now in Vall d’Hebron Institute of Oncology, Barcelona, Spain reported the results from an investigator-initiated trial on behalf of TOPARP investigators. TOPARP-B is a phase II randomised trial of the PARP inhibitor olaparib for mCRPC with DDR alterations. In general, DDR gene aberrations are found in 20-25% of mCRPC, either germline and/or somatic. BRCA2 is commonest altered DDR gene (10%) in that setting. PARP inhibitors are synthetic with many DDR gene aberrations including BRCA2, BRCA1, PALB2, ATM and CDK12.

The study team previously reported the results from TOPARP-A in The New England Journal of Medicine (Mateo et al. 2015) and showed antitumor activity of olaparib 400 mg BID in molecularly unselected mCRPC. At 2019 ASCO Annual Meeting, they reported results from TOPARP-B, a phase II trial in patients with mCRPC preselected for putatively pathogenic DDR alterations.

Patients with mCRPC who progressed after at least one taxane chemotherapy underwent targeted sequencing of tumour biopsies and were deemed eligible for the study when alterations, germline or somatic (mono- or bi-allelic) in any DDR gene were detected.

Patients were randomised 1:1 under a “pick-the-winner” design to 400 mg BID (the dose used in TOPARP-A) or 300 mg of olaparib BID (the dose used in the ovarian and breast cancers registration phase III trials), aiming to exclude ≤30% response rate (RR) in either arm. The primary endpoint RR was defined as radiological response according RECIST v1.1 and/or PSA50% fall and/or circulating tumour cells (CTC) count conversion (CellSearch; ≥5 to < 5), confirmed after four weeks. Analyses of RR per gene alteration subgroup was pre-planned. Secondary endpoints included PFS and tolerability.

In total, 98 patients (median age 67.6 years) were randomised, but 92 patients were treated and evaluable for the primary endpoint. Among these 70 were RECIST-evaluable, 89 were PSA50% evaluable and 55 were CTC-evaluable. All patients had progressed on androgen deprivation therapy; 99% were post-docetaxel, 90% post-abiraterone/enzalutamide, 38% post-cabazitaxel.

The overall RR was 54% in the 400 mg cohort and 37% in the 300 mg cohort.

With a median follow-up of 17.6 months, the overall median PFS (mPFS) was 5.4 months.

Subgroup analyses per altered gene identified indicated RRs for BRCA1/2 of 80% (mPFS 8.1 months), PALB2 57% (mPFS 5.3 months), ATM 37% (mPFS 6.1 months), CDK12 25% (mPFS 2.9 months), others (ATRX, CHEK1, CHEK2, FANCA, FANCF, FANCG, FANCI, FANCM, RAD50, WRN) 20% (mPFS 2.8 months).

The highest PSA50% RRs were observed in the BRCA1/2 (73%) and PALB2 (67%) subgroups.

The authors concluded that gene aberration type matters. In particular, RR and radiographic PFS (rPFS) differed between gene subgroups. In BRCA1/2-loss mCRPC, RR was approximately 80% with median rPFS longer than 8 months in the post-docetaxel and post-abiraterone/enzalutamide setting. In PALB2-mutated mCRPC, antitumour activity was similar to that for BRCA2. In ATM-mutated mCRPC, antitumour activity was observed, although more modest, but with longer rPFS that in remaining subgroups, but more data are required to understand importance of biological context. Dose may matter as well, but CDK12 aberrations were imbalanced between arms. Composite RR for 400 mg, but not 300 mg, fulfilled predefined criteria confirming TOPARP-A results. Increased RR and longer benefit with 400 mg BID were achieved, but there were 37% dose-reductions to 300 mg. The investigators announced ongoing work in terms of mono-allelic versus bi-allelic, somatic versus germline, and sub-clonality research.

Registration trials for PARP inhibitor therapy are ongoing in mCRPC based on TOPARP.

 

References

Kindler HL, Hammel P, Reni M, et al. Olaparib as maintenance treatment following first-line platinum-based chemotherapy (PBC) in patients (pts) with a germline BRCA mutation and metastatic pancreatic cancer (mPC): Phase III POLO trial. J Clin Oncol 37, 2019 (suppl; abstr LBA4). 

Golan T, Hammel P, Reni M, et al. Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. NEJM; Published online 2 June 2019.  DOI: 10.1056/NEJMoa1903387.

Mateo J, Porta N, McGovern UB, et al. TOPARP-B: A phase II randomized trial of the poly(ADP)-ribose polymerase (PARP) inhibitor olaparib for metastatic castration resistant prostate cancers (mCRPC) with DNA damage repair (DDR) alterations. J Clin Oncol 37, 2019 (suppl; abstr 5005).