Efficacy of PARP inhibitor therapy after targeted BRAF/MEK failure in advanced melanoma

Abstract

Modern advancements in targeted therapy and immunotherapy have significantly improved survival outcomes for advanced melanoma; however, there remains a need for novel approaches to overcome disease progression and treatment resistance. In recent years, PARPi therapy has shown great promise both as a single regimen and in combination with other therapeutics in melanoma. Here, we describe three unique cases of advanced BRAF V600 mutated melanoma that progressed on targeted BRAF/MEK agents that subsequently exhibited partial to near-complete responses to combinatory PARPi and BRAF/MEK inhibitors. This highlights both a potential synergy underlying this combinatory approach and its efficacy as a treatment option for patients with advanced melanoma refractory to targeted and/or immunotherapies. Prospective clinical trials are needed to explore this synergic effect in larger melanoma cohorts to investigate this combination for treating refractory advanced melanoma.

Fig. 1. Timeline correlating treatment and clinical response (using ctDNA and imaging) for patients 1 and 3.

A Patient 1. Top: CT-imaging 3 months after Olaparib initiation demonstrating resolution of a right common iliac node (previously 17 mm in short axis). Bottom: Graph depicting a timeline of administered systemic therapy and ctDNA changes during surveillance. White circle – ctDNA-negative; Black circle – ctDNA-positive; red triangle – progressive disease on imaging; light green triangle – partial response on imaging; dark green triangle – complete response on imaging; light purple rectangle – Binimetinib; light blue rectangle – combinatory Binimetinib and Olaparib; vertical dark blue line – initiation of radiotherapy. B Patient 3. Top: CT-imaging 3 months after Olaparib initiation demonstrating interval decrease in the size of a left lower lobe pulmonary nodule measuring 1.1 cm (previously measured 1.4 cm). Bottom: Graph depicting a timeline of administered systemic therapy and ctDNA changes during surveillance. Black circle – ctDNA-positive; red triangle – progressive disease on imaging; light green triangle – partial response on imaging; dark green triangle – complete response on imaging; light yellow rectangle – combinatory T-VEC and Nivolumab; purple rectangle – combinatory Encorafenib, Binimetinib, and Nivolumab; bright blue rectangle – combinatory Olaparib, Encorafenib, Binimetinib, and Nivolumab.