Treatment with a combination of olaparib with temozolomide was clinically effective in patients with relapsed small cell lung cancer (SCLC), according to the results of a recent study published in Cancer Discovery.
“Recently, targeting DNA damage repair by inhibition of poly [ADP-ribose] polymerase (PARP) has emerged as a potential therapeutic strategy in SCLC,” wrote study authors, led by Anna F. Farago, MD, PhD, Massachusetts General Hospital Cancer Center, Boston, MA. “Although SCLCs are not characterized by homologous recombination deficiency or mutations in BRCA1/2, PARP inhibitors have shown some activity in SCLC preclinical models and early phase trials.”
In this single-arm trial, the recommended phase 2 dose of oral olaparib (200 mg twice daily) plus temozolomide (75 mg/m2 daily on days 1-7 of a 21-day cycle) was determined according to the results of the phase 1 dose escalation study (n = 13). Subsequently, testing was expanded to include 37 additional patients for a total of 50.
Median progression-free survival (PFS) was 4.2 months (95% CI: 2.8-5.7); overall response rate, 41.7%, with 20 partial responses and no complete response; and median overall survival, 8.5 months (95% CI: 5.1-11.3).
“This combination showed significant clinical activity in patients with relapsed [SCLC], and warrants investigation in a randomized study comparing olaparib plus temozolomide with the standard-of-care option,” said Dr. Farago in an interview with the American Association for Cancer Research (AACR), which publishes Cancer Discovery.
Patient-derived xenografts (PDXs) supported clinical responses secondary to olaparib/temozolomide (OT), facilitating a 32-PDX co-clinical trial, which uncovered a relationship between low basal expression of inflammatory response genes and cross-resistance to OT and standard first-line chemotherapy (etoposide/platinum [EP]). These results portend novel treatment strategies in SCLC and provide a signature for tumors that are most likely to clinically respond.
With regard to patient characteristics, the number of prior lines of cancer therapy in participants was between one and seven (median: two). Platinum sensitivity was present in 72% of patients, and was defined as a chemotherapy-free interval from the completion of first-line therapy to the start of second-line therapy of ≥ 90 days.
The most common treatment-related adverse events were thrombocytompenia (68%), anemia (68%), and neutropenia (54%). Nevertheless, most adverse events were grades 1-2. Two grade 5 adverse events occurred, including pneumonia in cycle 1 and neutropenic sepsis in cycle 3.
On their own, PARP inhibitors do little against SCLC, per results of the UK STOMP trial, which failed to demonstrate prolongation in PFS for patients treated with olaparib maintenance. PARP inhibitors may synergize with agents that boost the number of single stranded DNA breaks (ie, chemo). The mechanics of this combination approach are supported even in homologous recombination and BRCA-intact tumors, per the finding that trapping PARP complexes to sites of single-stranded DNA breaks could result not only in repair failure, but the induction of double stranded breaks as well.
According to the Dr. Farago and colleagues, little available tissue exists for pre- and co-clinical analysis in SCLC research. Instead, first diagnosis is often based on little available aspirate tissue—with repeat biopsies after initial treatment usually not included as standard of care.
The authors have previously presented the generation of a panel of PDX models of SCLC that reflect patient genomics and sensitivity to EP.
“[In the current study], we develop and test the clinical activity of combination [OT] in patients with SCLC, and then apply a PDX panel to discover molecular signatures predictive of response to this treatment,” wrote the authors.
In the AACR interview, Dr. Farago also noted the following: “[SCLC], which accounts for about 15% of all lung cancers, historically has very poor outcomes, and novel treatment strategies are needed for this aggressive cancer type. This combinatorial therapy showed encouraging results in patients with relapsed SCLC, representing a new potential therapeutic strategy for these patients who typically have few effective treatment options.”