Intermittent PARP inhibitor regimen in ovarian cancer (IPIROC): A proof-of-concept exploratory pragmatic study (IPIROC#02) using generic rucaparib with pharmacodynamic assessment.

Abstract

e17597 Background: Affordability/toxicity of PARP inhibitors (PARPi) for ovarian cancer treatment is an unmet need in women with anemia/low BMI in LMICs. We generated proof-of-concept preclinical data showing durable parp inhibition with single dose rucaparib >72 hrs (doi.org/10.3390/cancers14225559). An academic/exploratory pilot study (CRUK-DBT funded) was conducted for optimal scheduling of generic rucaparib in India (Sponsor: KolGoTrg). Methods: IEC approval was obtained during Covid pandemic; CTRI could not be done. Platinum-sensitive (>3 months PFI) recurrent HGSC ovarian cancer patients were invited to participate if suited for PARPi monotherapy treatment. Bi-weekly rucaparib generic (1200 mg PO 72hours apart) was administered. Tolerability/toxicity/QOL and response-rate was assessed at 12 weeks, followed by physician’s-choice/patients’ preference for continuation of IPIROC regimen till progression, subsequent therapy or toxicity. Patient-public-involvement workshops and barrier identification for implementing a dose de-escalation study was conducted (KolGoTrg EASE matrix). ROCK trial MDT was conducted for virtual patient monitoring and data collection. GCLP validated PARP immunoblot assay (Newcastle University, UK) was standardised in India. Purity of the rucaparib (API, procured from BDR pharmaceuticals) was assessed using LCMS/MS in academic setting. Cell line studies confirmed durable PARP inhibition with generic rucaparib. PBMC/plasma was collected at pre-defined time points:0/24/72/168 hrs after the 1 st rucaparib dose to assess feasibility of PK/PD guided drug scheduling and clinical correlation. Results: 9 patients were enrolled (2022-2024); 4 women with large volume disease/ascites progressed at 12 weeks. 5/9 women continued IPIROC regimen till 24 weeks. All 3 patients with long duration of response at 68, 69 and 88 weeks respectively, showed durable PARP inhibition at 72/168 hrs by PD assay, while the non-responders did not. Further 3 women on daily frontline maintenance PARPi, requiring dose reduction due to toxicity/affordability, opted for IPIROC regimen outside trial and remained disease/toxicity free for 12 months continuing till 62,96 and 132 weeks respectively. No grade-3 haematological toxicity was recorded during the first 12 months on IPIROC regimen. Conclusions: Intermittent rucaparib regimen was acceptable and well-tolerated for >12 months in 6/12 patients (recurrent and frontline) with positive impact on QOL and affordability (1/4 th cost). PARP PD assay may identify suitable patients for personalised /optimal de-escalation scheduling providing proof-of-concept for a Phase 2 trial (IPIROC#03). Acknowledgement: GCIG mentors Michael Bookman, Amit Oza, Iain McNeish, Nicola Curtin and patient advocates Tina Mitra Mandira Chakraborty Sushmita Pal. Clinical trial information: KOLGO/IEC/071223-03 .