Patients with recurrent, platinum-resistant ovarian cancer have limited effective treatment options available, but a class of targeted antibody-drug conjugates (ADCs) represent a promising development for this population.

The treatment landscape for patients who experience disease progression following platinum-based chemotherapy include rechallenging with platinum chemotherapy or administering alternative targeted therapies, such as PARP inhibitors or VEGF inhibitors including bevacizumab (Avastin). However, there are limitations for these therapies including as use in their indicated use in the maintenance setting and/or the required presence of 

 mutations or homologous recombination deficiency [HRD] status for approved PARP inhibitors including olaparib (Lynparza), rucaparib (Pluvicto), and niraparib (Zejula). Further, agents such as bevacizumab are contraindicated for patients at risk of gastrointestinal perforation.

“[Approximately] 80% of patients with advanced ovarian cancer [have disease] recurrence,” Bradley J. Monk, MD, said in an interview with 

. “When they recur, we look at whether they recur in a setting that is eligible for platinum. We used to say that’s 6 months, or 183 days. We don’t say that anymore, because the most active agent in platinum-resistant recurrent ovarian cancer is platinum [chemotherapy]…. There’s good evidence that platinum doublets are better than single agents.” Monk is a professor of obstetrics and gynecology at The University of Arizona College of Medicine, Phoenix.

, Ursula A, Matulonis, MD, agreed with Monk, adding that retreatment is appropriate in some instances in combination with carboplatin, bevacizumab, or alone. “We’re learning that although patients may technically have a platinum-resistant ovarian cancer, meaning that they have progression within 6 months of last receipt of platinum, that you can reuse platinum again in the future if the patient's cancer responded to platinum.” Matulonis said. “Sometimes patients need a therapy to get them out of trouble [because] they have a bowel obstruction or symptomatic ascites. Reuse of platinum, even in the platinum-resistant setting, may be used and there are guidelines around this, but it hasn’t quite moved into what the FDA would consider standard paradigms for ovarian cancer.” Matulonis is chief of the Division of Gynecologic Oncology and the Brock-Wilson Family Chair at Dana-Farber Cancer Institute and a professor of medicine at Harvard Medical School, both in Boston, Massachusetts.

With poor prognosis and survival outcomes limited to 1 year post recurrence, investigators have focused on developing agents to fulfill the unmet need in platinum-resistant disease.

Biomarker-directed therapeutics have begun to gain traction in the field as actionable markers that would yield demonstrative results for this patient population. “[Over time] all patient if they recur, become platinum-resistant or ineligible,” Monk said. “That is the highest unmet medical need and the most exciting agent or agents in that are in development are antibody-drug conjugates.”

Establishing the Path Forward for ADCs in Ovarian Cancer

“The underlying thought behind ADCs is compelling. You have a very targeted therapy that goes to a specific cancer cell that overexpresses something that no other cells in the body do. The ADC delivers toxic poisons that we couldn’t normally give a patient [directly to the cancer cells],” Robert Wenham, MD, MS, said in an interview with 

“One of the Achilles’ heels of this program for several years was what links the antibody with the target to the poison itself. [Technological advances have made] linkers better so they release the poison when you want to. That has been what’s brought ADCs forward, because there have been a lot smart [individuals] working on this for a very long time, but it is the linker mechanism that has made this viable,” said Wenham, who is gynecologic oncologist and the chair of the Gynecologic Oncology Program at Moffitt Cancer Center in Tampa, Florida.

The development and success of ADCs in hematologic malignancies and breast cancer has resulted in their exploration in other solid tumors including ovarian cancer. Comprised of an antibody directed against a tumor antigen, a toxic payload, and a linker, investigators have sought to develop ADCs targeted against overexpressed antigens on tumor cells but not on normal tissue.

“[ADCs] are really interesting. They have the potential to change how we practice,” John Nakayama, MD, said in an interview with 

. Nakayama is an assistant professor, Department of Reproductive Biology at Case Western Reserve University in Cleveland, Ohio. “You have a monoclonal antibody, and then you have a linker, and then you have a payload. In theory, using that antibody, you can go after a particular a particular antigen to help localize what you are doing. And the idea behind that is if you’re localizing [the target], you can limit off-target effects [allowing you to] use a payload that’s more toxic, because it’s so much more targeted. That is precision medicine at its finest.”

In ovarian cancer, targets with agents under development include folate receptor alpha (FRα), NaPi2B, tissue factor, and others.

“In ovarian cancer there are not [many] targetable mutations except for 

 mutations [and the] biomarkers that we use in in ovarian cancer are genetic ones, and that can be HRD. The other markers we use histology and then platinum sensitivity or resistance,” Matulonis said. “But if I think that tissue expression, extracellular expression of proteins, [that] will allow a whole new therapy to be used, and that would be ADCs.”

In September 2021, the FDA approved the tissue factor–directed antibody and microtubular inhibitor conjugate, tisotumab vedotin-tftv (Tivdak), for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.

 The approval was based on data from the phase 2 innovaTV 204 trial (NCT03438396). Among 101 patients the objective response rate was 24% (95% CI, 15.9%-33.3%), with a median duration of response of 8.3 months (95% CI, 4.2-not reached).

“Tissue factor is expressed on almost all cervical cancer cells,” Monk said adding that this eliminates the need to test tumors for markers.

Only one ADC has thus far had data read out from a phase 3 evaluation. Mirvetuximab soravtansine, an ADC with a FRα-binding antibody, a cleavable linker, and maytansinoid DM4 payload, was evaluated in the single-arm phase 3 SORAYA trial (NCT04296890).

 Investigators assessed the efficacy of mirvetuximab soravtansine in patients with platinum-resistant ovarian cancer who had received 1 to 3 prior lines of therapy, experienced disease recurrence within 6 months of the last platinum-based regimen, and who have high FRα expression. This was defined as at least 70% of the cancer cells having 2+ or higher staining of FRα based upon the PS2 method.

Among 105 efficacy-evaluable patients the investigator-assessed overall response rate was 32.4% (95% CI, 23.6%-42.2%), including a 4.8% complete response rate. The disease control rate of 51.4% (95% CI, 41.5%-61.3%). Additionally, a 71.4% tumor reduction rate was reported. The investigator-assessed median duration of response was 6.9 months (95% CI, 5.6-9.7) with a median time to response of 1.5 months (range, 1.0-5.6).

The median investigator-assessed progression-free survival was 4.3 months (95% CI, 3.7-5.2). The median overall survival data were immature, but descriptive data showed a median 13.8-month survival (95% CI, 12.0-not estimable).

“We see with mirvetuximab soravtansine for patients [whose disease] overexpresses FRα, that is a good target because it’s overexpressed in the vast number of ovarian cancers. We’re seeing responses [with mirvetuximab soravtansine], even in combination, that are making us excited about potentially either adding to it chemotherapy or replacing chemotherapy altogether,” Wenham said.

Based on these data the FDA granted priority review to the biologic license application for mirvetuximab soravtansine. The agency is expected to make a decision on the application by November 28, 2022.

 Further, the phase 3 MIRASOL trial (NCT04209855) will assess mirvetuximab soravtansine vs investigator’s choice chemotherapy to confirm these findings.

“We are seeing very positive results with ADCs as a novel way of targeting ovarian cancer,” Matulonis said. “I see this as being a very fruitful [part of the] treatment paradigm, moving forward, starting with mirvetuximab.”

Finally, upifitamab rilsodotin (UpRi), which targets NaPi2b, a sodium-dependent phosphate transport protein is under investigation in this patient population. Other NaPi2b agents have not reached clinical success in prior development pursuits, however, in August 2020, UpRi received a fast-track designation from the FDA for the treatment of patients with platinum-resistant high-grade serous ovarian cancer who have received up to 3 prior lines of systemic therapy or those treated with 4 prior lines of systemic therapy regardless of platinum status.

The agent is under evaluation in the phase 1/2 UPLIFT registration trial (NCT03319628), with plans to enroll approximately 100 patients with platinum-resistant ovarian cancer with high NaPi2b expression and approximately 180 patients with platinum-resistant ovarian cancer in the pivotal experimental cohort. Early efficacy data from the trial showed that among the 75 evaluable patients, the ORR was 23%, including 2 patients who achieved a complete response. Of note, among 38 patients with NaPi2b high expression, defined as a tumor proportion score of at least 75, the confirmed ORR was 34% with a CR rate of 5% and a PR rate of 29%.

The phase 3 confirmatory trial UP-NEXT (NCT05329545) will compare UpRi with placebo as postplatinum maintenance therapy for patients with recurrent, platinum-sensitive, ovarian cancer. The trial is not yet recruiting.10 Additionally, investigators are looking at UpRi in combination with carboplatin in the phase 1/2 UPGRADE trial (NCT04907968), an umbrella study enrolling patients with platinum-sensitive ovarian cancer.

Testing and the Future of ADCs in the Landscape

Monk noted that testing for these markers will play a crucial role in getting patients to the right treatments at the right time. “The good news is, is that the FRα is relatively common, [approximately] 40% or so, and [if mirvetuximab soravtansine is] approved by the FDA, it will be integrated into all the biomarker platforms.” He noted that this will allow clinicians to have the report of actionable targets in front of them when they have discussions with their patients following platinum resistance.

Matulonis added that biopsies are critical at the time of diagnosis. “If a patient presents with advanced disease, which most of our patients do, and that patient is not deemed operable by a gynecologic oncology surgeon, then a biopsy must be done.”

Matulonis added that for FRα in particular, the target is still retained upon recurrence and therefore and additional biopsy is not needed at the time. “If there’s any question then a repeat biopsy could be done to assure the oncologist and the patient that that target is still present. But FRα has been shown to be retained at the time of recurrence,” she said. “I see this paradigm that as long as the expression of a specific protein or target is present different ADCs could be used.”

Nakayama noted the importance of testing as it will guide decision-making from maintenance and earlier treatment modalities. “I am a firm believer in both germline testing and somatic testing. Because that will help determine, you know, what is, you know, is this person candidate for maintenance therapy? And if so, which one? What I learned from experience… is be very cognizant of what you’re testing is telling you is extremely important.”

Nakyama supported that sentiment adding, “I think anything that we can do to build up our armamentarium in the platinum resistance setting is of critical value.”

Calo CA, O’Malley DM. Antibody-drug conjugates for the treatment of ovarian cancer. 

. 2021;21(7):875-887. doi:10.1080/14712598.2020.1776253

NCCN. Clinical practice guidelines in oncology. Ovarian cancer including fallopian tube cancer and primary peritoneal cancer, version 2.2022. Accessed July 19, 2022. 

https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf

Manzano A, Ocaña A. Antibody-drug conjugates: a promising novel therapy for the treatment of ovarian cancer. 

). 2020;12(8):2223. doi:10.3390/cancers12082223

FDA grants accelerated approval to tisotumab vedotin-tftv for recurrent or metastatic cervical cancer. FDA. Updated September 21, 2021. Accessed July 19, 2022. bit.ly/3upkVAr

Matulonis UA, Oaknin A, Pignata S, et al. Mirvetuximab soravtansine in patients with platinum-resistant ovarian cancer with high folate receptor alpha expression: characterization of antitumor activity in the SORAYA study. 

. 2022;40(suppl 16):5512. doi:10.1200/JCO.2022.40.16_suppl.5512

ImmunoGen announces acceptance of biologics license application for mirvetuximab soravtansine in ovarian cancer by US Food and Drug Administration with priority review. News release. ImmunoGen, Inc. May 23, 2022. Accessed July 19, 2022. bit.ly/3MV4Amt

A study of mirvetuximab soravtansine vs. investigator’s choice of chemotherapy in platinum-resistant, advanced high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancers with high folate receptor-alpha expression (MIRASOL). ClinicalTrials.gov. Updated June 16, 2022. Accessed July 19, 2022. https://clinicaltrials.gov/ct2/show/NCT04209855

Mersana Therapeutics receives FDA fast track designation for XMT-1536 for the treatment of patients with platinum-resistant ovarian cancer. News release. Mersana Therapeutics. August 11, 2020. Accessed July 19, 2022. bit.ly/3viEWLy

Interim data from the ovarian cancer expansion cohort and next steps for UpRi development plan. Mersana Therapeutics. September 10, 2021. Accessed July 19, 2022. bit.ly/3KchsM6

Upifitamab rilsodotin maintenance in platinum-sensitive recurrent ovarian Cancer (UP-NEXT) (UP-NEXT). ClinicalTrials.gov. Updated April 22, 2022. Accessed July 19, 2022. 

https://clinicaltrials.gov/ct2/show/NCT05329545

Supported by Immunogen. Content independently developed by 

Articles

Patients with recurrent, platinum-resistant ovarian cancer have limited effective treatment options available, but a class of targeted antibody-drug conjugates represent a promising development for this population.

ADCs Begin to Carve a Place in the Treatment Landscape for Ovarian Cancer

John Nakayama, MD, gynecologic oncologist, Allegheny Health Network, discusses the current treatment landscape of ovarian cancer and where he hopes the field advances in the future.

When a patient is diagnosed with ovarian cancer, it is important to assess what steps to take regarding surgery, chemotherapy, optimal debulking, and/or future treatment regimens, which can include chemotherapy with carboplatin and paclitaxel, or bevacizumab (Avastin), Nakayama says. These are important considerations, since they can affect which treatment regimens patients could receive in later lines of therapy, Nakayama adds. Moreover, it is important to open a dialogue with patients about the length and expectations of therapies, Nakayama emphasizes.

It is also vital to ensure that genetics are done early for patients, including both germline and somatic testing, since they can help determine if a patient is a candidate for maintenance therapy, Nakayama continues. If better screening tests were available, oncologists could diagnose patients at an earlier stage. Currently, the majority of patients are diagnosed at an advanced stage, Nakayama adds.

Additionally, as the treatment landscape evolves, it is important to consider which patients should receive PARP inhibitors, and though individual practice may vary, patients with a 

 mutation should get a PARP inhibitor, Nakayama adds.

When looking to the future of ovarian cancer, personalized medicine will assist in accessing all the different gene sequences within a panel, Nakayama expands. By trying to leverage this information, this assists in utilizing an artificial intelligence-based approach to better predict how well a patient will do, Nakayama concludes.

Videos

John Nakayama, MD, discusses the current treatment landscape of ovarian cancer and where he hopes the field advances in the future.


Dr. Nakayama on the Current Treatment Landscape of Ovarian Cancer

Bradley J. Monk, MD, FACS, FACOG, professor, Division of Gynecologic Oncology, Arizona Oncology (US Oncology Network), University of Arizona College of Medicine, Creighton University School of Medicine at St. Joseph’s Hospital, medical director, Gynecologic Program, US Oncology Research Network, co-director, GOG Partners, discusses the role platinum-based chemotherapy in recurrent ovarian cancer, plus emerging antibody-drug conjugates in the space.

Since the majority of patients with ovarian cancer eventually recur, determining if they are eligible for platinum-based chemotherapy is vital, even in patients who might have been historically considered to have platinum-resistant recurrent ovarian cancer, Monk says. Patients are no longer described as platinum resistant; instead, they platinum ineligible, and emerging evidence that platinum doublets are better than single agents, Monk adds. Moreover, if a patient is not a candidate for platinum-based chemotherapy, then the most active non-platinum agents to consider are weekly paclitaxel or bevacizumab (Avastin), though if a PARP inhibitor was used in the beginning of therapy, bevacizumab is the preferred option, Monk adds.

Although there is not a bevacizumab/PARP inhibitor combination approved in for the treatment of patients who have recurred, bevacizumab can be utilized multiple times, Monk continues. Importantly, it is necessary to be aware of the risk of gastrointestinal perforation with multiple lines of therapy and understand the risk factors, Monk says.

All patients who recur becoming platinum ineligible over time and eventually die of their disease, creating the highest unmet medical need in ovarian cancer, Monk explains. However, ADCs remain some of the most promising agents emerging in ovarian cancer, as multiple clinical trials have shown the benefit of these agents, Monk adds. Agents such as mirvetuximab soravtansine (IMGN853), upifitamab rilsodotin (XMT-1536), and others have shown promise, and they remain under evaluation, Monk says.

Another unique factor includes ovarian clear cell carcinomas harboring an 

 mutation, which is also being studied, Monk adds. Oncologists continue to observe the time to recurrence in platinum eligibility, plus the number of lines of therapy and molecular signatures, Monk concludes.

Bradley J. Monk, MD, FACS, FACOG, discusses the role platinum-based chemotherapy in recurrent ovarian cancer, plus emerging antibody-drug conjugates in the space.


Dr. Monk on Platinum Ineligibility and Emerging ADCs in Ovarian Cancer

Robert Wenham, MD, MS, FACOG, FACS, gynecologic oncologist, chair, the Gynecologic Oncology Program, Moffitt Cancer Center, discusses the role of antibody-drug conjugates (ADCs) in ovarian cancer.

The underlying thought behind ADCs is compelling, since the agents can target biomarkers expressed only on cancer cells before delivering a payload to attack the cancer and preserve health cells, Wenham says. As the technology behind ADCs has improved, they have become more realistic options for use in ovarian and other cancers, Wenham adds.

In ovarian cancer, the ADC mirvetuximab soravtansine has been evaluated for patients with folate receptor alpha–high, platinum-resistant ovarian cancer. FRα is an ideal target since it is overexpressed in many patients with ovarian cancer, Wenham explains.

Ongoing clinical trials in ovarian cancer are exploring a variety of combination therapies, including platinum-based chemotherapy combinations, Wenham continues. Combinations examining platinum with anti-VEGF and immunotherapy are being evaluated to see if they can become viable options in ovarian cancer, Wenham adds. Moreover, additional ADCs are being explored as single agents and in various combinations, Wenham explains. Although it is unknown which ADC target will be the most successful for ovarian cancer, it is hoped that several will be found through future trials, Wenham says.

Regarding PARP inhibitors in ovarian cancer, there have been an abundance of data favoring patients harboring 

 mutations, Wenham emphasizes. The phase 3 SOLO2 trial (NCT01874353) investigated olaparib (Lynparza) vs placebo as maintenance therapy for patients who had a complete or partial response to platinum-based chemotherapy, and it demonstrated an overall survival benefit with olaparib, Wenham says. Various therapies are being explored to attempt to overcome PARP resistance and make more patients respond, Wenham continues.

Considering the emergence of ADCs and PARP inhibitors, the importance of biomarker testing has been amplified for patients with ovarian cancer, Wenham explains. By identifying 

 mutations or homologous recombination repair deficiency, more targeted therapies can be selected, and more than half patients with ovarian cancer will test positive for these biomarkers, Wenham concludes.

Robert Wenham, MD, MS, FACOG, FACS, discusses the role of antibody-drug conjugates in ovarian cancer.


Dr. Wenham on the Role of ADCs in Ovarian Cancer

Ursula A. Matulonis, MD, physician, chief, Division of Gynecologic Oncology, Dana-Farber Cancer Institute, Brock-Wilson Family chair, professor of Medicine, Harvard Medical School, discusses the current treatment landscape of recurrent ovarian cancer.

There is considerable overlap in the treatment paradigms for patients with newly diagnosed ovarian cancer and recurrent ovarian cancer, Matulonis says. Though some patients may develop platinum-resistant ovarian cancer, defined as progression within 6 months of their last treatment with platinum-based chemotherapy, it is possible to utilize platinum again if there was a response, Matulonis explains.

When treating a patient who could respond to platinum-based chemotherapy, options include a carboplatin doublet with or without bevacizumab (Avastin), Matulonis continues. Typical doublets with bevacizumab may include carboplatin/paclitaxel or carboplatin/gemcitabine, Matulonis explains.

Regarding PARP inhibitors, the phase 3 SOLO2 (NCT01874353), NOVA (NCT01847274), and AERIAL3 (NCT01968213) trials all demonstrated progression-free survival benefits in patients with ovarian cancer who responded to platinum-based chemotherapy before receiving a PARP inhibitor as maintenance, Matulonis says. When considering the use of a PARP inhibitor, patients can be classified as 

-mutated, homologous recombination deficient/

 wild-type, and homologous recombination proficient/BRCA wild-type, though patients in the latter category tend to have the least benefit from PARP inhibitors, Matulonis explains.

FDA approvals for this patient population have been seen mainly with PARP inhibitors in different spots within patient treatment, including niraparib (Zejula), olaparib (Lynparza), and rucaparib (Rubraca), Matulonis continues. Additionally, bevacizumab can be utilized up-front, in platinum sensitive-recurrence, and then platinum-resistant recurrence, Matulonis explains.

One of the newer medications in the space is mirvetuximab soravtansine, an antibody-drug conjugate that has shown promising efficacy in heavily pretreated patients with folate receptor alpha–high, platinum-resistant ovarian cancer, Matulonis says. The agent is currently under review by the FDA for accelerated approval, Matulonis emphasizes.

Aromatase inhibitors are being examined in women with low-grade serous ovarian cancer. These cancers have shown to not be consistently chemotherapy sensitive, but they are usually estrogen receptor–positive and hormonally sensitive, Matulonis explains. An ongoing phase 3 trial (NCT04095364) trial is investigating the aromatase inhibitor, letrozole (Femara), with or without carboplatin plus paclitaxel, in patients with stage II-IV low-grade serous ovarian cancer, Matulonis concludes.

Ursula A. Matulonis, MD, discusses the current treatment landscape of recurrent ovarian cancer.


The Emerging Landscape & Novel Biomarkers in Ovarian Cancer | Supplements and Featured Publications

ADCs Begin to Carve a Place in the Treatment Landscape for Ovarian Cancer

Dr. Nakayama on the Current Treatment Landscape of Ovarian Cancer

Dr. Monk on Platinum Ineligibility and Emerging ADCs in Ovarian Cancer

Dr. Wenham on the Role of ADCs in Ovarian Cancer

Dr. Matulonis on the Current Treatment Landscape of Recurrent Ovarian Cancers