Promising Durvalumab Plus Olaparib Combination Being Explored in Metastatic Urothelial Cancer

In an interview with <em>Targeted Oncology</em>, Jonathan Rosenberg, MD, discussed the ongoing study of durvalumab plus olaparib in patients with metastatic urothelial cancer and other studies that have lain the groundwork for this combination.

Jonathan Rosenberg, MD

The ongoing randomized phase II study of durvalumab (Imfinzi) plus olaparib (Lynparza) as first-line treatment for patients with locally advanced or metastatic urothelial cancer (NCT03459846) is aiming to fill an unmet need by offering a new option for patients who are platinum-ineligible, who can generally only be treated with immunotherapy.

Based on previous studies in other disease states, the investigators sought out to see if a durvalumab combination could trigger higher response rates than durvalumab alone. Also, because of the high rates of mutation in DNA repair genes in urothelial cancer, these patients may be more likely to respond when poly ADP ribose polymerase (PARP) inhibition is a part of their therapy.

Further rationale for the study was to answer questions about how to activate responses in DNA repair genes. Research suggests that there may be heightened activity regardless of DNA repair gene genotype and it may be possible to activate genomic stress in the cancer cells by inhibiting DNA repair processes, which will ultimately trigger antitumor responses.

The randomized, double-blind, comparative, global study is enrolling patients who are unable to receive cisplatin or carboplatin-based chemotherapy and are ages 18 and older. Thus far, no findings have been reported from this study, but Jonathan Rosenberg, MD, has noted that the combination has not shown any concerning toxicity signals.

In an interview withTargeted Oncology, Rosenberg, chief, Genitourinary Medical Oncology Service, Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center (MSKCC), discussed the study of durvalumab plus olaparib in patients with metastatic urothelial cancer and other studies that have lain the groundwork for this combination.

TARGETED ONCOLOGY:Can you summarize the current treatment landscape for patients with metastatic urothelial cancer?

Rosenberg:This trial is enrolling patients who are platinum-ineligible, meaning that they are not candidates for cisplatin or carboplatin-based chemotherapy in locally advanced or metastatic urothelial cancer.

This is a patient population for whom immunotherapy is a standard option, regardless of PD-L1 status. This category of patients was defined by the FDA when they limited the labels of atezolizumab (Tecentriq) and pembrolizumab (Keytruda) based on the interim analyses of the KEYNOTE-361 and IMvigor130 trials, which showed that only PD-L1—high patients did well on those trials when treated with single-agent checkpoint therapy. The FDA limited the labels of those 2 approved drugs for PD-L1–high patients who were candidates for platinum chemotherapy, while if they were platinum-ineligible, there was no restriction around PD-L1 status.

This study targets that latter population, for whom immunotherapy is a standard option regardless of PD-L1 status.

TARGETED ONCOLOGY:What data do we have on the effectiveness of durvalumab monotherapy for patients with metastatic urothelial cancer?

Rosenberg:We don't have much data in the untreated patient population. This study will give us both information on durvalumab monotherapy as well as durvalumab plus olaparib. Durvalumab in urothelial cancer was approved in the post-platinum setting, based on the single-arm phase II study which showed a response rate of 17%. That was sufficient evidence for accelerated FDA approval for platinum-refractory patients.

To my knowledge, there are no large first-line data sets that have been reported for cisplatin-ineligible or platinum-ineligible patients.

DANUBE is the randomized phase II trial of durvalumab or durvalumab plus tremelimumab or first-line platinum-based chemotherapy. It has completed accrual but no findings have been reported to date. They only accrued patients who were platinum eligible because one of their arms is platinum-based chemotherapy.

Overall, this is a patient population for which there's an unmet need and for which there's very little data on any of these agents in the first-line setting.

TARGETED ONCOLOGY:What was the rationale for combing durvalumab with olaparib in this study? Does the combination show synergy?

Rosenberg:There are data in other diseases that are provocative and interesting. In urothelial cancer, there's a high mutation burden. There are high rates of mutations in DNA repair genes compared with other cancers, which is in roughly 20% to 25% of patients. Many of those are mutations in homologous recombination that might be predictive and lead to olaparib sensitivity.

In addition, there is preclinical evidence that suggests that you can induce stress within the cancer cells that may predispose the response to immunotherapy when you inhibit DNA repair processes.

Multiple fronts suggest that there might be increased activity regardless of DNA repair gene genotype, but perhaps it is heightened in those patients with DNA repair defect. Our study is designed to look at both of those questions because the analysis is stratified by the presence or absence of DNA repair mutation, so that we will be able to answer those questions in a more detailed, prospective fashion.

TARGETED ONCOLOGY:What is the safety profile with this combination? Are there any adverse events of special interest or concern?

Rosenberg:From what I've seen, there doesn’t seem to be any adverse events of special interest that are unique to the combination. The toxicity profiles seem to be similar to what you might expect from either drug alone.

To my knowledge, there are no new and unexpected toxicities that have revealed themselves in this study.

TARGETED ONCOLOGY:What other combinations are possible for targeting these tumors, in your opinion?

Rosenberg:There are many clinical trials right now that are looking at both cisplatin-ineligible as well as platinum-ineligible patients. There are large randomized phase III trials, one of which will report out very soon, looking at combinations of chemotherapy with immunotherapy in platinum-eligible patients, like IMvigor130.

For cisplatin-ineligible patients, there are clinical trials testing things like FGFR inhibitors in combination with immunotherapy. There are trials testing antiangiogenics in combination with immunotherapy. Some trials are looking at antibody—drug conjugates in combination with immunotherapy in this population. Many of those trials don't break out a separate platinum-ineligible category, which is nebulously defined at the moment. But, many of those patients are often eligible for "cisplatin-ineligible" clinical trials.

TARGETED ONCOLOGY:What other ongoing trials are of interest in urothelial cancer?

Rosenberg:There are some promising data in the treatment-refractory population on the drug called enfortumab vedotin, which received an FDA breakthrough designation. We hope that based on the phase II data, which was reported at ASCO and published in theJournal of Clinical Oncologyin June, that this drug will be approved in 2020. That clinical trial was EV-201, which was a single-arm phase II study that was led, in part, at MSKCC.

We also have combinations of enfortumab vedotin being tested in clinical trials with other agents. There's an upcoming report at ESMO 2019 of enfortumab vedotin plus pembrolizumab with some encouraging results. That will be presented by Dr Chris Hoimes.

There are potentially interesting novel approaches with cellular therapies that are starting to be investigated in bladder cancer for patients with metastatic disease. Those are in very early phases right now and we don't have data yet on those.