Research Efforts Seek to Unlock the Potential of PARP Inhibition in Thoracic Malignancies

PARP inhibitors have been broadly and efficaciously utilized in oncology for years, with several agents garnering FDA approval in breast cancer, ovarian cancer, and prostate cancer; that same efficacy has yet to be observed in thoracic malignancies, such as non–small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).

However, ongoing studies with biomarker-selected cohorts may help to identify those subsets who might confer benefit from these agents, Sandip Patel, MD, said in a presentation during the 22nd Annual International Lung Cancer Congress®, a program hosted by Physicians’ Education Resource^®, LLC.¹

The way in which PARP inhibitors work can be defined by 2 distinct mechanisms: synthetic lethality and PARP trapping. The former leads to chromosomal catastrophe in the cancer cells, which makes them unable to survive or replicate.2 With PARP trapping, although this is more nuanced and varied amongst the different inhibitors, DNA strands are trapped and the replication of cancer cells is blocked, according to Patel.

“Predictive biomarkers for PARP inhibition sensitivity often involves having a baseline mutation that already effects ability to conduct DNA repair” Patel, an associate professor in the Department of Medicine at UC San Diego Health, explained. “These drugs were FDA approved initially for [those with] germline mutations in BRCA1 or BRCA2, followed by some somatic mutations initially in breast and ovarian cancers. There have been data in pancreatic and prostate cancer, as well. As such, the idea that this can be a pan-histology biomarker was initially met with enthusiasm. However, over time, it looks like some of these efficacy changes are context specific.”

In terms of genomic correlates of response to these agents, certain pathways have been found to be more strongly associated with synthetic lethality than others.3 Those pathways include:

• The BRCA1/BRCA2 pathway, which repairs single- and double-strand breaks in DNA
• The SLFN11 pathway, which results in the killing of cells undergoing replication stress
• The loss of heterozygosity (LOH), which is an assay that can be used to look for homologous recombination deficiency (HRD)

“There are multiple mechanisms by which you can have an underlying issue in terms of DNA repair in cancer cells, for which a PARP inhibitor can be that second ‘key’ on the nuclear summary to lead to chromosomal catastrophe,” Patel noted.

Rationale for PARP in Thoracic Malignancies

BRCA1/2 mutations have been found to be present in approximately 14% of patients with NSCLC, and 12% of those with SCLC.⁴ As such, if these mutations prove to be viable therapeutic targets as they have in other cancer types, PARP inhibition could have potential as the third leading targeted treatment in thoracic malignancies, after EGFR and KRAS G12C targeted therapies, Patel added.

In the phase 1/2 ATF-07 trial (NCT02412371) the PARP inhibitor veliparib (ABT-888) was examined in combination with concurrent chemoradiotherapy to induce DNA damage in patients with stage III NSCLC.⁵ The regimen yielded some activity, with an objective response rate (ORR) of 64.3%. “These are reasonable rates of activity but nothing that substantially moved the needle to want to incorporate [this into practice], and there was toxicity that was predominantly related to cytopenias,” Patel said.

Similarly, the Lung-MAP SWOG S1400G trial (NCT02154490) examined talazoparib (Talzenna) in patients with advanced, refractory squamous cell lung cancer whose tumors harbor BRCA1/2, ATM, ATR, and PALB2 mutations. The agent yielded an ORR of just 4%.⁶

“The most elite responder was HRD negative, and so the biomarker was not exactly predicting the limited biologic effect we saw here,” Patel noted.

Modest efficacy was observed, however, in the Lung-MAP SWOG S1900A trial (NCT03845296) that examined rucaparib in the second-line treatment of patients with BRCA1/2-mutant, LOH advanced NSCLC.⁷ Results from the study demonstrated a potential benefit in patients with homozygous BRCA mutations, although the overall efficacy was muted, according to Patel.

Efforts to Incorporate PARP Inhibition in SCLC

SCLC remains a disease where targeted therapeutic approaches have yet to be established, despite the disease being characterized by mutations in DNA repair.⁸ Due to this, ongoing studies are examining the potential for PARP inhibition in this patient population.

“The thought has been to combine temozolomide [Temodar], a drug commonly used in glioblastoma but that can also be used in SCLC, in combination with PARP inhibitors as a rational, biologically-designed approach in patients with refractory SCLC,” Patel said.9 “However, although some patients had benefit, overall, the response rates were limited.”

In a multicenter phase 2 clinical trial (NCT01638546), investigators compared the use of temozolomide plus veliparib or placebo in the second- or third-line treatment of patients with relapsed SCLC.⁹ Results indicated a significant difference in ORRs between those who received veliparib/temozolomide vs those who were given temozolomide alone, at 39% and 14%, respectively (P = .016). However, no significant difference was observed with regard to the 4-month progression-free survival rates in the investigative and control arms, at 36% and 27%, respectively (P = .39).

Similarly, temozolomide was examined in combiantion with olaparib (Lynparza) in patients with refractory SCLC, and although some responses were observed, the durability of those responses was limited, Patel said. Additionally, the toxicity associated with this treatment was prohibitive to some patients, according to Patel.¹⁰

What’s Next with PARP Inhibition in Lung Cancer?

An area of research that has yielded promising outcomes in other disease types, such as ovarian cancer, is the combination of immunotherapeutic agents with PARP inhibitors, Patel said. In fact, recent data have shown that even those patients with BRCA wild-type mutations are experiencing responses to PARP inhibition combined with PD-1 inhibition, that would be expected with either therapy alone.

“This is an area of potential interest across other tumor types,” Patel concluded. “The mechanism by which this biology leads to benefit, and potentially durable benefit, for patients is still unclear, but it is an exciting avenue of research.”

References

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9. Pietanza MC, Waqar SN, Krug LM, et al. Randomized, double-blind, phase II study of temozolomide in combination with either veliparib or placebo in patients with relapsed-sensitive or refractory small-cell lung cancer. J Clin Oncol. 2018;36(23):2386-2394. doi:10.1200/JCO.2018.77.7672
10. Farago AF, Yeap BY, Stanzione M, et al. Combination olaparib and temozolomide in relapsed small-cell lung cancer. Cancer Discov. 2019;9(10):1372-1387. doi:10.1158/2159-8290.CD-19-0582