AstraZeneca and MSD’s Lynparza (olaparib) has been approved in Japan for the treatment of advanced ovarian, prostate and pancreatic cancers….The three approvals authorise Lynparza for:...maintenance treatment after platinum-based chemotherapy for patients with BRCAm curatively unresectable pancreas cancer.

Lynparza is a cancer medicine used on its own for:...continuing treatment of pancreatic cancer, in patients with mutations in BRCA1 or BRCA2 genes, that is metastatic (has spread to other parts of the body) and has not worsened after at least 4 months of platinum-based chemotherapy.

Lynparza is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated...adult patients with deleterious or suspected deleterious gBRCAm metastatic pancreatic adenocarcinoma...

Lynparza is indicated as monotherapy for the...maintenance treatment of adult patients with deleterious or suspected deleterious gBRCAm metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen.

Recommendations…Treatment Options After First-Line Therapy…In patients who have a germline BRCA1 or BRCA2 mutation and who have received first-line platinum based chemotherapy without disease progression for at least 16 weeks, options for continued treatment include chemotherapy or PARP inhibitor olaparib...

...two BRCA1 and two BRCA2 pancreatic cancer pts...Treatment with olaparib shows activity in cancer pts with a HR gene mutation and is well tolerated.

Non Supportive Evidence:...O vs P among patients with a gBRCAm and mPaC whose disease had not progressed during PBC, there was no statistically significant difference....OS was similar for the O and P groups (median 19.0 and 19.2 mo, respectively; HR 0.83 favoring O; 95% CI 0.56–1.22; p= 0.3487). OS at 36 mo was 33.9% for O and 17.8% for P. Median PFS2 was 16.9 mo for O vs 9.3 mo for P (HR, 0.66; 95% CI 0.43–1.02; p= 0.0613).

Multivariate analyses demonstrated a PFS improvement with olaparib versus placebo when adjusted for baseline factors, while sensitivity analyses showed no indication of bias….Maintenance olaparib provided a consistent, significant PFS benefit versus placebo in patients with mPC and a gBRCAm who had not progressed on PBC, irrespective of clinical factors, geographical location or other baseline factors.

Patients aged ≥65 years with a gBRCAm and metastatic pancreatic cancer can derive long-term PFS benefit (≥2 years) and durable tumour response from maintenance olaparib treatment.

RM-PFS was significantly longer with olaparib, with a between-treatment difference of 4.8 months (P=0.009; Table)….The corresponding mean QA-PFS was significantly longer with olaparib vs placebo….Consistent with the primary PFS analysis of the POLO trial, RM-PFS and QA-PFS were significantly longer with maintenance olaparib than with placebo. As demonstrated by the findings of the TWiST analyses, the PFS benefit observed with olaparib in pts with a gBRCAm and mPaC persists even when symptoms of toxicity are considered.

We conducted a randomized, double-blind, placebo-controlled, phase 3 trial to evaluate the efficacy of olaparib as maintenance therapy in patients who had a germline BRCA1 or BRCA2 mutation and metastatic pancreatic cancer....The median progression-free survival was significantly longer in the olaparib group than in the placebo group (7.4 months vs. 3.8 months; hazard ratio for disease progression or death, 0.53; 95% confidence interval [CI], 0.35 to 0.82; P = 0.004).

Documented mutation in gBRCA1 or gBRCA2 that is predicted to be deleterious or suspected deleterious

In summary, the BRCA1 cohort includes 9 patients with pancreatic cancer and 18 patients with other tumor types. As far as the size of the cohorts allows, the CBR appears to be similar between the two groups: 55.5% (2 PR and 3 SD) for the pancreatic cancer patients and 66.6% (1 PR and 11 SD) for the other cancer patients. The partial remission was in a patient with gallbladder cancer, out of six patients with this cancer included in the study....In BRCA1/2-mutated cancers, olaparib can be active and produce durable responses in various cancer types.

The POLO study (NCT02184195) demonstrated a significant progression-free survival (PFS) benefit for active maintenance olaparib (O) relative to placebo (P) for patients (pts) with metastatic pancreatic cancer and a germline BRCA mutation... we present an exploratory extended OS analysis, carried out 12 months after the final OS analysis (DCO3)....The OS result at DCO3 remained similar to that at DCO2 (HR: 0.79; 95% CI: 0.55–1.15)....Investigator-PFS, TDT, TFST and TSST were longer for O than for P (table).

We analyzed the impact of exposure to olaparib on OS from the start of I-line treatment in a cohort of 114 Italian gBRCA PC pts….In the entire cohort, OS from the start of I-line treatment for metastatic disease was significantly (p=0.02) longer in pts who had been exposed to olaparib in any treatment line (n=53; Table).... A statistically significant difference in OS favoring gBRCA PC pts who were exposed to olaparib in any line of treatment was observed in the M+ cohort (p=0.0025), in the no PD cohort (p=0.049), and in the M+/no PD cohort (n=73, p=0.019)....In gBRCA PC pts, exposure to olaparib in any line of treatment in a real-world setting significantly impacts on OS, further supporting its use in the current indication (I-line maintenance after platinum-based CHT).

Pts were enrolled based on either a previously identified gBRCAm status from a local test result and subsequently confirmed by central testing, or a prospectively identified gBRCAm. Pts received maintenance olaparib...From a total of 151 variants, frameshift mutations were most frequent (gBRCA1m 69.6%, gBRCA2m 71.4%) followed by nonsense mutations (gBRCA1m 6.5%, gBRCA2m 17.1%)....The efficacy (PFS) of olaparib vs placebo in the different subgroups are shown in the table.

From a total of 151 variants, frameshift mutations were most frequent (gBRCA1m 69.6%, gBRCA2m 71.4%) followed by nonsense mutations (gBRCA1m 6.5%, gBRCA2m 17.1%)….PFS benefit was consistent across a heterogenous spectrum of gBRCAm and with the previously reported full analysis set.

Nine different cancer types were included: prostate (n=11), breast (n=4), ovarian (n=2), pancreatic (n=3), colorectal (n=2), biliary tract (n=2), kidney (n=1), adrenal gland (n=1) and endometrial (n=1). The primary endpoint was clinical benefit (CB: objective response or stable disease (SD) ≥ 16 weeks). CB was observed in pts with both somatic and germline BRCA alterations and across tumor types.

The objective response rate (ORR) for all evaluable patients was 23%. One patient who carried a deleterious germline BRCA2 mutation had a durable clinical response lasting more than four years.

Individuals (age ≥ 18 years) with a confirmed germline loss-of-function BRCA1 or BRCA2 mutation deemed deleterious or suspected deleterious by local practice before consent and advanced solid tumor were enrolled....Responses to olaparib were observed across different tumor types associated with germline BRCA1/2 mutations.

We observed the patient had a good progression-free survival (7.4 months); the lesion of the pancreas was classified as partial disease through Olaparib treatment, which indicated significant shrinkage….The targeted therapy Olaparib showed early signs of potential in treating PC in patients with mutations of the BRCA genes.