Ovarian Cancer Trials Expand Research Across Subtypes

Christina Fotopoulou, MD, PhD

Trials in the ovarian cancer space are constantly addressing a challenging patient population that experts like Christina Fotopoulou, MD, PhD, say were neglected in the past.

Recently, trials in this space have focused on patients with platinum-resistant, platinum-refractory ovarian cancer, and homologous recombination deficiency (HRD)-negative ovarian cancer through the evaluation of non-replicating adenoviral vectors, PD-L1 inhibitors, VEGF inhibitors, PARP inhibitors, antibody drug conjugates, and more.

The OVAL study (NCT03398655) sought to compare VB-111 and paclitaxel vs placebo and paclitaxel in adult patients with recurrent platinum-resistant ovarian cancer. Although results were negative, these data can help inform future research considering the use of adenoviruses.¹

The DUO-O study (NCT03737643), though not fully finished, showed positive data with the addition of immunotherapy in patients with newly-diagnosed, advanced ovarian cancer.² Further, a third study (NCT03748186) evaluating luveltamab tazevibulin (STRO-002) showed meaningful data a 43.8% overall response rate (ORR), median duration of response (DOR) of 5.4 months, and median progression-free survival (PFS) of 6.6 months. As a result of this study, the phase 2/3 REFRaME trial plans to initiate.³

“We have experienced, in the last years especially, a plethora of new agents in ovarian cancer. We have never seen so many positive trials in ovarian cancer with so many new targeted agents and so many new aspects of care that we can explore,” Fotopoulou, chair in gynecological cancer surgery in the department of surgery and cancer, faculty of medicine, Imperial College London, told Targeted Oncology^TM, in an interview.

In the interview, Fotopoulou highlighted multiple trials that have brought important lessons to the ovarian cancer space.

Targeted Oncology: Can you discuss some of the novel trials being researched in the ovarian cancer space?

Fotopoulou: We had 3 new trials. One was the phase 3 OVAL study with VB-111 in combination with paclitaxel vs paclitaxel [alone], which has shown encouraging results in a previous phase 1/2 study. However, it failed at the end to show any significant OS and PFS results in the platinum-resistant/refractory population. It is an adenovirus so it's a bit more tricky to manipulate and a bit more tricky to target into the areas we need it, so a broader implementation would have been theoretically challenging. This doesn't mean that the efforts in that regard have stopped. The principal chief investigator, Rebecca Arend, MD, said that she wishes to continue the efforts and of course, to explore other, alternative avenues to see whether adenoviruses of that sort would be beneficial in patients with ovarian cancer.

The second study is a very large multicenter prospective randomized phase 3 study with durvalumab [Imfinzi], a PD-L1 inhibitor, bevacizumab [Avastin], a VEGF inhibitor, and PARP inhibitors, vs bevacizumab alone. These were the 2 main arms that were the primary analysis; there was also a second arm with bevacizumab and durvalumab. The primary end point was to see whether there was a survival benefit in the [intent-to-treat] and [homologous recombination deficiency]-positive population.

This study is the first study in ovarian cancer, the first IO second-line cancer [study], to show a significant prolongation of the PFS with the HR of 0.68 for the HRD-negative population, which has always been a very challenging target group. So far, it is a group where only the PRIMA [NCT02655016] and the DUO-O study [NCT03737643] have shown a benefit. Very interestingly, we see that the hazard ratio in both studies is exactly the same with 0.68. It was very interesting to see it; even though the HR is the same, the difference is the triplet. One has a triplet therapy and the other only 1 [drug], meaning of course that there are also different associations with morbidity and toxicity and heterogenic complications, etc.

The third study was a study with luveltamab tazevibulin, an antibody drug conjugate, which was in a promising phase 1 study and has shown a significant overall and duration of response rate, PFS, and that has shown a difference. Now, they proceed to a phase 2 study in the REFRaME study to check the dose-escalation principles and then take it from there.

How have recent developments in ovarian cancer changed or grown over the past few years?

We have experienced, in the last years especially, a plethora of new agents in ovarian cancer. We have never seen so many positive trials in ovarian cancer with so many new targeted agents and so many new aspects of care that we can explore. However, what I also emphasize is that we still fail to have concrete biomarkers and concrete individualization algorithms of which patient groups will benefit from. Currently, it's like we are in a new playground with new kids. We need to put them a bit under perspective and to put them a bit more in order for a more individualized treatment perspective.

How do you individualize these treatments when you're treating patients?

In ovarian cancer, we have learned in the last year that there are biomarkers. There are new things that we explore. What we are not very good at yet is finding the path. For example, in some studies like MIRASOL [NCT04209855], there are different catalogs for the folate receptor alpha, and the HRD scores. Now, even in my institution, we're doing extensive research to see that there is a very big heterogeneity, spatial heterogeneity within the same patient, even for the HRD scores. There are still many things that we don't understand. For example, in more common cancers like breast cancer, there are concrete algorithms where this patient with that signature will get this [specific] treatment, but not yet [in ovarian cancer]. And in surgery, it is even less. Currently, we'll just operate everybody the same way, which would definitely need to change.

Where do you expect the field to move next?

I think everybody's enthusiastic about ovarian cancer. Ovarian cancer has been a silent killer and a deadly disease for decades. Currently, we see that even though we haven't seen a significant difference yet in the actual cure rates, we’ve seen a massive prolongation of the survival for patients, and we have turned the disease to a chronic disease. We are getting much better. If you compare the results of [recent] studies to survival data of 10 years ago, there is a big difference. This is very motivating for us and encouraging for our patients. I think the future will be all in these new agents and to put them into little boxes and into little algorithms that will be targeted and allocated to the right patients.

What other studies do you anticipate will be practice changing?

There is the SHAPE trial [NCT01658930] which is a study that we have long expected. It is a study of radical hysterectomy vs simple hysterectomy and pelvic node dissection in low-risk cervical cancer, meaning patients with a tumor of less than 2 centimeters and less than 10 millimeters stromal invasion. The study has shown that there is absolutely no benefit in the radical approach. The next step will be that the guidelines change. The next thing would be that the whole approach in how we treat cervical cancer changes and also equally, not just in hysterectomy, but also in trachelectomy, because trachelectomy is a principle where we remove the cervix together for a fertility sparing approach in patients with lower than 2 centimeter tumors. It's not necessarily true with the perimetrium anymore since we have seen that in these low-risk patients, the perimetrium resection has no benefit. It just increases the complications.

REFERENCES:

1. Arend RC, Monk BJ, Shapira-Frommer R, et al. Randomized controlled phase III trial of weekly paclitaxel ± ofranergene obadenovec (VB-111) for platinum-resistant ovarian cancer (OVAL Study/GOG 3018). J Clin Oncol. 2023;41(suppl 16):LBA5506.

2. Harter P, Trillsch F, Okamoto A, et al. Durvalumab with paclitaxel/carboplatin (PC) and bevacizumab (bev), followed by maintenance durvalumab, bev, and olaparib in patients (pts) with newly diagnosed advanced ovarian cancer (AOC) without a tumor BRCA1/2 mutation (non-tBRCAm): results from the randomized, placebo (pbo)-controlled phase III DUO-O trial. J Clin Oncol. 2023;41(suppl 17):5505-5505.

3. Sutro Biopharma announces updates from STRO-002, luveltamab tazevibulin (Luvelta), phase 1 dose-expansion study and registrational plans in advanced ovarian cancer. News release. Sutro Biopharma, Inc. January 9, 2023. Accessed August 29, 2023. https://yhoo.it/3GzHyIK