2005 Background: Although the Stupp protocol (radiotherapy + temozolomide (TMZ)) remains the cornerstone of glioblastoma (GBM) first line treatment after surgery (resection or biopsy), the prognosis is still poor. PARP inhibitors, such as olaparib, may enhance the efficacy of radiotherapy and TMZ by amplifying their cytotoxic effects. We implemented a phase 1/2 trial to assess safety and efficacy of olaparib combined with TMZ concomitant with intensity modulated radiotherapy (IMRT) as a first line treatment in GBM patients (pts) following biopsy or subtotal resection. The phase 1 conducted in 30 pts concluded the recommended phase 2 dose (RP2D) of olaparib was 100 mg Q12H Day (D) 1-3, in concomitant with the Stupp protocol. We herein report results of the phase 2a. Methods: Pts were treated with adjuvant IMRT (60 Gy/30 fractions/6 wks), with concurrent daily oral TMZ (75 mg/m²). For the maintenance period (MT) from 4 wks after IMRT, pts received TMZ (150 mg/m², D 1-5 every 28 days, for 6 cycles). Oral olaparib was started at the RP2D the same day as IMRT, concurrently with the Stupp protocol and continued up to disease progression or unacceptable toxicity. The trial was conducted according to a two-step Case and Morgan design and required 55 assessable pts (37 in interim analysis), to assess the 12-month (mo) overall survival (OS) rate expected to be higher than 57%. Final Z-statistic>1.235 will confirm efficacy. All pts who received olaparib at RP2D were included in the analysis, including pts of the phase 1 step. Results: From 2020 to 2024, 68 pts were enrolled and treated in the phase 2a: 41 (60%) men, median age 59 yrs range 20-70. 67 pts (98%) had GBM and 1 (2%) IDH mutated anaplastic astrocytoma. Biopsy-only was performed for 27 pts (40%). ECOG performance status 0 for 34 pts (51%), 1 for 28 pts (42%) and 2 for 5 (7%). 11 pts (16%) stopped the study before MT, including 4 for grade 3-4 hematological toxicity. Among the 57 pts who began the MT, 5 stopped the treatment for hematological toxicity. 3 pts remain on treatment. Interim analysis conducted in March 2024 in 41 patients, with median follow-up o 7.6 mo, led pursuing the study, with a 12-mo OS rate of 72.9% 95%CI: 56.7-93.9. At final analysis, after median follow-up of 17.2 mo, 48 deaths (71%) were observed. Median OS was 18.4 mo and 12-mo OS rate of 69.1% 95%CI: 59-81 (H0 rejection according to Z-statistic=1.29). Among hematological toxicities of interest, thrombocytopenia grade ≥ 3 was observed in 5 pts, neutropenia grade 4 in 4 pts, febrile neutropenia grade ≥ 3 in 1 pt and anemia grade ≥ 3 in 4 pts. One toxic death was observed (febrile aplasia). Conclusions: Intermittent olaparib (100 mg Q12H D1-3) combined with the Stupp protocol appears to be beneficial to improve survival of poor prognosis nonresected/partially resected GBM pts, with a safety profile quite similar to that of the standard chemoradiotherapy. Clinical trial information: NCT03212742 .
Stefan et al. (Wed,) studied this question.
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