What is the recommended treatment regimen for the combination of olaparib (Poly (ADP-ribose) polymerase (PARP) inhibitor) and radiation therapy in patients with cancer, as investigated in the SWOG (Southwest Oncology Group) 1706 trial?

SWOG 1706: Olaparib and Radiation Therapy Combination

Critical Finding: No SWOG 1706 Trial Data Available

After comprehensive review of all provided evidence, there is no trial designated as "SWOG 1706" investigating olaparib combined with radiation therapy. The evidence base contains multiple trials examining olaparib-radiation combinations in various cancers, but none are identified as SWOG 1706 1, 2, 3, 4.

Evidence-Based Recommendations for Olaparib-Radiation Combinations (Based on Available Trials)

Non-Small Cell Lung Cancer (NSCLC)

The maximum tolerated dose of olaparib with concurrent radiation therapy in NSCLC is 25 mg once daily, and this combination carries substantial risk of severe pulmonary toxicity. 3

• Phase I trial established MTD at olaparib 25 mg once daily with 66 Gy/24 fractions (2.75 Gy/fraction) 3
• Adding concurrent cisplatin (6 mg/m²/day) exceeded MTD due to hematologic and late esophageal dose-limiting toxicities 3
• Critical safety concern: 18% grade 5 (fatal) pulmonary adverse events occurred at latency of 1-2.8 years across all dose levels 3
• Exploratory analyses suggest association between severe pulmonary toxicity and radiation dose to lungs 3
• Despite toxicity, efficacy signals were promising: 2-year locoregional control 84%, median overall survival 28 months in locally advanced NSCLC 3

Glioblastoma (Older/Poor Performance Status Patients)

Olaparib 200 mg twice daily can be safely combined with hypofractionated brain radiation therapy (40 Gy in 15 fractions) in patients aged ≥70 years or with poor performance status. 4

• PARADIGM trial phase 1 established recommended phase 2 dose: olaparib 200 mg twice daily 4
• Maximum tolerated dose was not reached in 3+3 dose escalation 4
• Only 1 dose-limiting toxicity reported (grade 3 agitation) 4
• Median overall survival: 10.8 months; progression-free survival: 5.5 months 4
• Cognitive function was not adversely affected by the combination (Mini Mental State Examination monitoring) 4
• This regimen is specifically for patients unsuitable for radical chemoradiation 4

Soft-Tissue Sarcoma

Olaparib 100 mg twice daily with concurrent radiation therapy is feasible for soft-tissue sarcoma but requires stringent patient selection to avoid severe complications. 2

• French Sarcoma Group phase Ib trial established recommended phase 2 dose: 100 mg twice daily 2
• Radiation regimens: 50 Gy (25 fractions) for resectable tumors or 59.4 Gy (33 fractions) for unresectable tumors 2
• Efficacy in operable patients: 33% favorable histological response, 90.5% local relapse-free survival at 1 year 2
• Inoperable tumors: median progression-free survival 7.7 months, 20% partial responses, 60% stable disease 2
• Critical exclusion criteria: avoid patients with tumors involving critical vascular structures or high surgical risk 2
• Grade 3 radiation dermatitis occurred in 34.1% of patients 2
• Two grade 5 (fatal) toxicities occurred (4.8%) 2

Mandatory Hematologic Monitoring for All Olaparib-Radiation Combinations

Complete blood count monitoring must be intensified to at least every 2 weeks when combining olaparib with radiation therapy, particularly during and immediately after radiation. 5

• Anemia is the most common dose-limiting toxicity of olaparib (9-46% depending on severity) 5
• Radiation therapy to cranium/spine causes grade 3-4 hematologic toxicity in approximately one-third of patients 5
• Skeletal radiation specifically associated with hematologic toxicity due to bone marrow involvement 5
• NCCN guidelines require: careful CBC monitoring, type and screen availability, transfusion support readiness, and dose reductions for severe anemia 6, 5
• Patients receiving skeletal radiation should be considered at substantially elevated risk when also receiving olaparib 5

Critical Safety Considerations Across All Disease Sites

Radiation therapy is not contraindicated based on ATM heterozygote status, and current consensus supports offering radiation when indicated without dose modification for ATM mutation carriers. 6

• Limited evidence supports PARP inhibitor use in ATM-mutated cancers; olaparib showed no responses in 8 ATM-mutated metastatic breast cancer patients in TBCRC 048 trial 6
• PARP inhibitors are DNA-interacting drugs with potential to induce hematologic malignancies; long-term follow-up for myelodysplastic syndrome and acute myelogenous leukemia is needed 7

Preclinical Rationale Supporting Combination Therapy

Neoadjuvant olaparib (7 days ending 48 hours prior to radiation) improved radioresponse by decreasing tumor hypoxic fraction in homologous recombination-proficient breast cancer models. 1

• Olaparib 50 mg/kg bid for 7 days before 12 Gy radiation increased in vivo growth delay and decreased ex vivo clonogenic survival 1
• Mechanism: olaparib may modify tumor microenvironment by targeting hypoxic tumor clonogens and/or increasing tumor-associated vasodilation to improve oxygenation 1
• Purely neoadjuvant olaparib (ending before radiation starts) may improve therapeutic window with limited toxicity 1