乌鸦传媒

Studies across a range of solid tumor types, including breast, ovarian, and pancreatic cancers, have demonstrated clinical benefit with poly (ADP-ribose) polymerase (PARP) inhibition, particularly in patients harboring alterations in DNA damage response (DDR) genes such as BRCA1/2. A growing body of evidence also suggests that PARP inhibition may be effective in a broader range of DDR alterations.

Recently, a single-arm, open-label phase II study, published in , evaluated the antitumor activity of single-agent olaparib 300 mg twice a day in a molecularly selected subgroup of 19 patients with metastatic urothelial cancer (mUC). The results showed that no patient achieved an objective response, although six patients had stable disease lasting a median of 7.69 months. Overall, the median progression-free survival (PFS) was 1.9 months, and median overall survival was 9.5 months.

"Despite the relatively high prevalence of DDR gene alterations in urothelial cancer, single-agent PARP inhibition in the setting of predominantly platinum-resistant disease demonstrates negligible clinical activity," wrote Matthew D. Galsky, MD, of Tisch Cancer Institute of Icahn School of Medicine at Mount Sinai in New York City, and colleagues. "Combination regimens with PARP inhibition and immune checkpoint blockade in the platinum-naïve setting have demonstrated s and may warrant furthers study."

In the cohort, 10 patients (52.6%) had alterations in homologous recombination (HR) genes, including eight (42.1%) who had pathogenic BRCA2 mutations, and two who carried alterations in other HR genes. Nine patients (47.4%) had received previous cisplatin chemotherapy.

One patient treated with olaparib for 14.1 months had a PFS of 16.1 months, the longest reported. This finding suggests that olaparib played a role in prolonging disease control, the authors said, adding that the patient had , which is known to impair HRR and confer sensitivity to PARP inhibition.

In the following interview, Galsky, director of Genitourinary Medical Oncology and co-director of the Center of Excellence for Bladder Cancer, discussed the findings in greater detail.

Are DDR gene alterations relatively common in metastatic urothelial carcinoma?

Galsky: Yes, but so far, exploiting this potential therapeutic vulnerability has proven challenging.

How do your findings compare with those from other studies?

Galsky: Our results are consistent with other trials exploring PARP inhibition in patients with metastatic urothelial carcinoma. One of these, the , explored the PARP inhibitor rucaparib in unselected patients who had progressed despite up to two lines of previous systemic therapy. Among 95 patients, only 10 of whom had data confirming a deleterious alteration in a DNA damage repair pathway gene, there were no confirmed responses. By contrast, the , which explored the role of switch maintenance rucaparib versus placebo, reported that rucaparib was associated with an improved PFS of 35.1 versus 15.1 weeks although only one patient had a partial response.

In your study, six patients achieved stable disease while on olaparib. What are the implications of this?

Galsky: BRCA2 alterations seemed to be enriched in the patients who were on study treatment for the longest duration, but the small sample size precludes any definitive associations to be established.

What do you consider the most likely explanation for the modest activity of PARP inhibition in mUC and why?

Galsky: Given that platinum-based chemotherapy is standard first-line treatment for metastatic urothelial cancer, or at least was when our trial was conducted, I think that overlapping mechanisms of resistance to platinum chemotherapy and to PARP inhibitors likely accounted for the modest activity. In other tumor types, resistance to platinum chemotherapy is strongly predictive of resistance to PARP inhibitors and although there are almost certainly non-overlapping mechanisms of resistance, there are also overlapping mechanisms of resistance.

Do you think other genomic alterations in mUC might confer greater sensitivity to PARP inhibition in patients not previously treated with platinum-based chemotherapy?

Galsky: I think some of the alterations that we tested, such as BRCA2 alterations, likely do confer sensitivity to PARP inhibition in platinum-naïve patients. One would need to test that concept, however, with a sufficient sample size. Given that non-platinum-based chemotherapy has become a standard option for cisplatin-ineligible patients with metastatic urothelial cancer -- for example, enfortumab vedotin plus pembrolizumab -- that concept could probably still be tested.

What's next for your research?

Galsky: We are continuing to explore how molecular alterations in genes involved in DNA response and repair can be therapeutically exploited, particularly in the setting of immune checkpoint blockade. In the , there was a signal suggesting improved outcomes in patients with urothelial cancers harboring DDR alterations treated with PD-L1 blockade plus olaparib versus PD-L1 blockade alone.

Read the study here and expert commentary about it here.