Ovarian Cancer Landscape Evolving With Encouraging SOLO2 Analyses, Novel Agents

Michael J. Birrer, MD, PhD

The PARP inhibitor olaparib (Lynparza) continued to show significant promise as an agent for patients with platinum-sensitive ovarian cancer and germline BRCA mutations, according to secondary analyses of the SOLO2 study presented at the 2017 ASCO Annual Meeting.

Patient-reported outcomes demonstrated an improvement in progression-free survival (PFS) with no decrement in health-related quality of life (QOL) during maintenance therapy with olaparib.¹ During a mean follow-up of 12 months, the average score on the Functional Assessment of Cancer Therapy-Ovarian Trial Outcome Index did not change significantly from baseline among patients treated with olaparib and did not differ from the control group. However, the duration of time with disease-related symptoms or toxicity was found to be significantly longer in olaparib-treated patients.

Moreover, a second abstract focused on an expanded analysis of adverse events (AEs), which was the first clinical evaluation of a tablet formulation of olaparib.² Prior studies used a capsule formulation. The analysis focused on greater detail of the initial SOLO2 AEs with the new olaparib formulation— nausea, vomiting, fatigue/asthenia, and anemia—all of which were consistent with prior studies of olaparib.

OncLive: SOLO2 was a pivotal trial of olaparib in ovarian cancer. Can you give some background on this study?

What QOL data were presented at the 2017 ASCO Annual Meeting?

AE data were also presented. Can you comment?

In an interview with OncLive during the 2017 ASCO Annual Meeting, Michael J. Birrer, MD, PhD, who is now medical director at the University of Alabama at Birmingham Comprehensive Cancer Center, discussed some of the exciting data presented at the meeting—especially with olaparib in SOLO2—and what other emerging advancements are poised to transform the landscape.Birrer: SOLO2 is an exciting time. The efficacy data was presented at the 2017 Society of Gynecologic Oncology meeting a couple of months ago. The SOLO2 data follows and looks a lot like Study 19 but, in fact, the data are even better. Therefore, the placebo arm had a median PFS of about 5 months. This is consistent with all of the placebo-controlled maintenance trials, which are between 4 and 5 months. However, the olaparib-treated arm was about 19 months. That is a whopping prolongation of PFS, and that was the investigator analysis. If you look at the independent radiologic review, it actually goes out until about 30 months. It is a very positive trial. It is going to the FDA, and I have no doubt that this drug will be approved [in the maintenance setting].The QOL data basically follows with what you would expect. Patients who are on olaparib maintenance do well. There was a concern about the formulation because the old capsule requires the patients to take 16 pills a day. That is a lot of pills; the tablet form is a much lower [amount]. Thus far, it looks like the tablets are going to be a home run.The AE data are what you would expect from a PARP inhibitor. There is some fatigue and nausea [reported]. The nausea disappears after a while, and there is some mild myelosuppression. That is about it.

There have been recent developments with mirvetuximab soravtansine. What is the promise with this drug?

This fits Dr Birrer’s definition of a good maintenance drug. It is easy to take, it’s convenient, it has minimal side effects, and it is efficacious. One of the hot new drugs for the treatment of ovarian cancer is mirvetuximab soravtansine, which is an antibody-drug conjugate targeting the folate receptor alpha. This drug has gone through phase I testing and into an expansion cohort—with what I would say are very impressive data. Response rates in platinum-resistant ovarian cancer are in the range between 40% and 50%. The toxicity profile is outstanding. There is, essentially, no bone marrow suppression and no neuropathy. There is an interesting toxicity involving blurred vision, but it is completely manageable and completely reversible.

A lot of us have worked on this project, in this program, and are very excited about it. Based on that data, it is now being investigated in an FDA registration trial called FORWARD I, which is a randomized trial between standard of care, which would be single-agent chemotherapy, doxorubicin, topotecan, or weekly paclitaxel, versus single-agent mirvetuximab soravtansine.

What is it about mirvetuximab soravtansine that sets it apart from other agents in ovarian cancer?

It is now open; the accrual to date is somewhere between 20 and 30 patients, but between 60 and 80 sites are going to have it open. I suspect the accrual is really going to pick up. We are very excited about that. It is a wonderful example of the technology of antibody-drug conjugates. To date, they have had a mixed track record, but mirvetuximab soravtansine, in particular, is working the way it was planned. It is very targeted against the folate receptor alpha. To date, there are no real off-target effects that we can tell.

What is the FORWARD II trial seeking to answer?

Folate receptor alpha is overexpressed in about 70% of high-grade serous ovarian cancers, so it is a very relevant target. Then, if you look at the tissues in the human body that express folate receptor alpha, there is some expression on type II alveolar cells. There is some low-level expression in renal tubular cells. We don’t think the renal tubular cell expression means anything; we have seen no renal toxicity. There is some signal with some low-level toxicity in the lung—some pneumonitis—which may be an on-target toxicity. Essentially, it is a wonderfully guided missile, if you will, to the cancer. The next-generation of trials with mirvetuximab soravtansine is to combine it with other agents, so the company along with its advisors—including me—have chosen the relevant drugs in ovarian cancer. For platinum-sensitive disease, it’s been combined with carboplatin. That combination is particularly active and you don’t see the systemic activity you see with taxanes. We have combined it with bevacizumab (Avastin), which is an active drug, in the treatment of ovarian cancer. That is ongoing.

What about mechanisms of resistance?

Most recently, it has been combined with pembrolizumab (Keytruda), which is a hot drug. We are not quite sure of its activity in ovarian cancer, but combining those 2 make sense. One of the real advantages of mirvetuximab soravtansine is that the toxicity is narrow and different; you don’t see any overlapping toxicities with any of these drugs. There is no synergistic toxicity or cumulative bone marrow toxicity. I remain very bullish on this drug. We were lucky enough to get an NCCN grant to explore the mechanisms of resistance to this drug. Obviously, some patients respond and some don’t respond. Some respond and develop resistance. There is very little known about the mechanisms of resistance.

What do we know about the clinical characterization of long-term survivors in ovarian cancer?

The early data we have developed is unpublished. At least 1 mechanism is the downregulation of the target, folate receptor alpha, essentially begins to disappear on the cells. What is intriguing about that is that, at some point, we will be able to reverse that and upregulate the target again, in which case the tumor should become re-sensitized. There will be more to follow. This is a collaboration that we are doing. Jalid Sehouli, MD, is a spectacular researcher in Berlin who has been able to develop this consortium throughout all of Germany looking at long-term survivors of ovarian cancer. It works well with work we are doing at Massachusetts General Hospital, because we have a Department of Defense Consortium for Long-Term Survival that is essentially focused on ovarian cancer tumors and the psychosocial aspects of patients who lived more than 10 years with ovarian cancer.

It is an area that is completely unstudied. What’s different about these patients who lived that long with what is normally a terrible disease? Many of these patients have active disease. However, it’s indolent. It responds to chemotherapy. Therefore, understanding that will eventually allow us to better understand the patients who don’t do as well and potentially develop new therapies for them.

References

1. Friedlander M, Gebski V, Gibbs E, et al. Health-related quality of life (HRQOL) and patient-centered outcomes with maintenance olaparib compared with placebo following chemotherapy in patients with germline (g) BRCA-mutated (m) platinum-sensitive relapsed serous ovarian cancer (PSR SOC): SOLO-2 Phase III trial. J Clin Oncol. 2017;35 (suppl; abstr 5507).
2. Lederman JA, Lortholary A, Penson RT, et al. Adverse events (AEs) with maintenance olaparib tablets in patients (pts) with BRCA-mutated (BRCAm) platinum-sensitive relapsed serous ovarian cancer (PSR SOC): Phase III SOLO2 trial. J Clin Oncol. 2017;35 (suppl; abstr 5518).