Phase II Study of Maintenance Rucaparib in Patients With Platinum-Sensitive Advanced Pancreatic Cancer and a Pathogenic Germline or Somatic Variant in BRCA1, BRCA2, or PALB2.

PURPOSE: Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi), is approved as maintenance therapy for patients with advanced pancreatic cancer (PC) and a germline BRCA1 or BRCA2 pathogenic variant (PV). This investigator-initiated, single-arm phase II study assessed the role of the PARPi rucaparib as maintenance therapy in advanced PC with germline or somatic PV in BRCA1, BRCA2, or PALB2. PATIENTS AND METHODS: Eligible patients had advanced PC; germline (g) or somatic (s) PVs in BRCA1, BRCA2, or PALB2, and received at least 16 weeks of platinum-based chemotherapy without evidence of platinum resistance. Chemotherapy was discontinued and patients received rucaparib 600 mg orally twice a day until progression. The primary end point was the progression-free survival (PFS) rate at 6 months (PFS6). Secondary end points included safety, ORR, disease control rate, duration of response, and overall survival. RESULTS: Of 46 enrolled patients, 42 were evaluable (27 gBRCA2, seven gBRCA1, six gPALB2, and two sBRCA2). PFS6 was 59.5% (95% CI, 44.6 to 74.4), median PFS was 13.1 months (95% CI, 4.4 to 21.8), and median overall survival was 23.5 months (95% CI, 20 to 27). The PFS at 12 months was 54.8%. ORR of the 36 patients with measurable disease was 41.7% (3 complete responses; 12 partial responses; 95% CI, 25.5 to 59.2), and disease control rate was 66.7% (95% CI, 49.0 to 81.4). Median duration of response was 17.3 months (95% CI, 8.8 to 25.8). Responses occurred in patients with gBRCA2 (41%, 11 out of 27), gPALB2 (50%, 3 out of 6), and sBRCA2 (50%, 1 out of 2). No new safety signals were noted. CONCLUSION: Maintenance rucaparib is a safe and effective therapy for platinum-sensitive, advanced PC with a PV in BRCA1, BRCA2, or PALB2. The finding of efficacy in patients with gPALB2 and sBRCA2 PVs expands the population likely to benefit from PARPi beyond gBRCA1/2 PV carriers.

Structural basis for allosteric PARP-1 retention on DNA breaks.

The success of poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors (PARPi) to treat cancer relates to their ability to trap PARP-1 at the site of a DNA break. Although different forms of PARPi all target the catalytic center of the enzyme, they have variable abilities to trap PARP-1. We found that several structurally distinct PARPi drive PARP-1 allostery to promote release from a DNA break. Other inhibitors drive allostery to retain PARP-1 on a DNA break. Further, we generated a new PARPi compound, converting an allosteric pro-release compound to a pro-retention compound and increasing its ability to kill cancer cells. These developments are pertinent to clinical applications where PARP-1 trapping is either desirable or undesirable.

Synthesis and Characterization of Neutral Ligand α-Diimine Complexes of Aluminum with Tunable Redox Energetics.

The synthesis and full characterization of a series of neutral ligand α-diimine complexes of aluminum are reported. The compounds [Al(LAr)2Cl2)][AlCl4] [LAr = N, N'-bis(4-R-C6H4)-2,3-dimethyl-1,4-diazabutadiene] are structurally analogous, as determined by multinuclear NMR spectroscopy and solid-state X-ray diffraction, across a range of electron-donating [R = Me (2), tBu (3), OMe (4), and NMe2 (5)] and electron-withdrawing [R = Cl (6), CF3 (7), and NO2 (8)] substituents in the aryl side arm of the ligand. UV-vis absorption spectroscopy and electrochemistry were used to access the optical and electrochemical properties, respectively, of the complexes. Both sets of properties are shown to be dependent on the R substituent. Density functional theory calculations performed on the [Al(LPh)2Cl2)][AlCl4] complex (1) indicate primarily ligand-based frontier orbitals and were used to help support our discussion of both the spectral and electrochemical data. We also report the reaction of the LPh ligand with both AlBr3 and AlI3 and demonstrate a different reactivity profile for the heavier halide relative to the lighter members of the group.