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PARP inhibitor plus trabectedin shows promise for sarcoma

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TOMAS clears path to phase 2

The phase 1b TOMAS trial by Grignani et al. showed that PARP inhibitor combination therapy may be a safe and effective option for patients with sarcoma, and a phase 2 study is warranted, according to Benjamin A. Nacev, MD, and William D. Tap, MD.

PARP inhibitors mitigate DNA damage repair, suggesting potential for synergistic combinations with DNA-damaging anticancer agents. Unfortunately, previous combinations have revealed toxicity issues.

“The first clinical example of this approach was the combination of the alkylating drug temozolomide and the PARP inhibitor rucaparib, which was hampered by dose-limiting myelosuppression,” Dr. Nacev and Dr. Tap wrote in an editorial in The Lancet Oncology.

In the TOMAS trial, Grignani et al. assessed a combination of trabectedin and the PARP inhibitor olaparib. Preclinical data showed synergistic activity in sarcoma cell lines, and the authors predicted tolerable myelosuppression with trabectedin.

Their predictions yielded promising results: Approximately one-third of patients with soft-tissue sarcoma were progression free at 6 months. Although myelosuppression did occur, the adverse event profile was tolerable.

As drug synergisms are biologically complex, “a key success of the TOMAS trial is the effective use of exploratory pharmacodynamic endpoints including PARP1 expression, PARylation, and mutational status of the DNA damage repair pathway.”

“For example, efficacy in the TOMAS trial correlated with PARP1 expression, with greater 6-month progression-free survival in the high PARP1 expression group than the low expression group.”

“The TOMAS investigators should be commended for doing the important bench-to-bedside approach of rationally designing and testing a drug combination to leverage available active drugs. We agree with the authors’ call for further investigation of trabectedin and olaparib in a randomised phase 2 trial in soft tissue sarcoma.”

William D. Tap, MD is chief of the Sarcoma Medical Oncology Service and Benjamin A. Nacev, MD is a third-year medical oncology/hematology fellow at Memorial Sloan Kettering Cancer Center in New York. Dr. Tap reported personal fees from Eli Lilly, Novartis, Eisai, and others. These comments are adapted from their accompanying editorial .



A combination of trabectedin and the PARP inhibitor olaparib may be a safe and effective therapy for patients with sarcoma, the recent TOMAS trial found.

High PARP1 expression was associated with treatment response, reported Giovanni Grignani, MD, of the Medical Oncology_Sarcoma Unit at Istituto di Ricovero e Cura a Carattere Scientifico in Candiolo, Italy, and his colleagues.

PARP inhibitors prevent repair of DNA damage, suggesting potential synergisms with DNA-damaging anticancer agents. Preclinical models support this strategy; however, clinical trials have found that toxicities restrict doses below antitumor activity levels.

“In view of these findings, trabectedin could be an ideal drug to use in combination with PARP1/2 inhibitors for two reasons: its favourable haemopoietic toxicity profile and its unique mechanisms of action,” the authors wrote in The Lancet Oncology. Trabectedin bends the minor groove of DNA toward the major groove, which activates PARP1 in an attempt to repair the damage. Preclinical trials showed that a PARP inhibitor such as olaparib would block this PARP1 activation, ultimately resulting in a more robust response than with either drug alone.

The phase 1b, open-label TOMAS trial involved 50 patients with sarcoma who had experienced disease progression after standard therapy. The study was divided into two cohorts: dose-escalation and dose-expansion. Patients received a median of four cycles of therapy with a median follow-up of 10 months (some patients are still undergoing treatment). The primary endpoint was maximum tolerated dose. The investigators also evaluated pharmacokinetics, pharmacodynamics, and various response measures.

Although adverse events occurred, these were manageable, and the authors concluded that the combination is safe for further investigation. The most common grade 3 or higher adverse events were lymphopenia (64%), neutropenia (62%), thrombocytopenia (28%), anemia (26%), hypophosphatemia (40%), and alanine aminotransferase elevation (18%). The maximum tolerated dose (recommended phase 2 dose) was olaparib 150 mg twice daily and trabectedin 1.1 mg/m2 every 3 weeks.

“These doses allowed us to minimize the need for dose reductions and continue treatment for as long as tumour control was maintained,” the authors wrote. Previous treatments impacted tolerability. The researchers noted that “patients who had received more than two lines of therapy had a higher risk of developing dose-limiting toxicities than those patients who had been treated with only one line of therapy.”

Overall, 14% of patients responded to therapy. Six-month progression-free survival was more common in patients with soft tissue sarcoma (38%) than other tumor types. More patients with high PARP1 expression achieved 6-month PFS compared with patients who had low PARP1 expression (59% vs. 8%; P = .01).

“The combination of olaparib and trabectedin exploits the potential of two different first-in-class drugs and shows tolerability and activity in homologous repair-proficient tumors,” the authors concluded.

They are planning two phase 2 studies in the future; one “comparing trabectedin alone versus the combination of trabectedin and olaparib, stratifying patients according to PARP1 expression,” and an “after-platinum-failure study of patients with ovarian cancer regardless of patients’ BRCA1/2 and BRCAness status.”

The TOMAS trial was funded by the Italian Association for Cancer Research, the Foundation for Research on Musculoskeletal and Rare Tumors, the Italian Ministry of Health, and PharmaMar. The authors reported compensation from Lilly, Novartis, Bayer, Eisai, Amgen, and others.

SOURCE: Grignani et al. Lancet Oncol. 2018 Sep 11. doi: 10.1016/S1470-2045(18)30438-8.

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