‘Explosion’ of FDA approvals made ‘significant’ impact in ovarian cancer

ByRyan McDonald

John K. Chan, MD

Ovarian cancer accounts for 2.5% of all cancer cases in women across the United States, making it the eighth most common cancer in women, according to data from the American Cancer Society and the World Cancer Research Fund.

Although occurrence rates are considered small, ovarian cancer still accounts for 5% of cancer deaths because of its relatively low survival rate.

The 5-year relative survival rate for all types of ovarian cancer is 47% but increases significantly to 92% if the cancer is found in its earliest stage and treated before the cancer has had the opportunity to spread outside the ovary.

However, only 15% of all ovarian cancers are found during the early stages of development, according to statistics from the American Cancer Society.

Although the combination of cytoreductive surgery and standard chemotherapy has been shown to be effective, approximately 70% of patients experience relapse and long-term survival remains poor.

As a result, there has been a call for an extended development of novel treatment strategies.

But according to John K. Chan, MD, Denise and Prentis Cobb Hale Endowed Chair at the California Pacific Medical Center, Regional Cancer Center Director of Gynecologic Oncology at the California Pacific-Palo Alto Medical Foundation Research Institute and lead principal investigator of the Sutter Cancer Research Consortium, the last few years have brought many exciting developments in the treatment of ovarian cancer and could be leading to an era of precision medicine.

“Ovarian cancer used to be limited to a broad stroke standard treatment, which meant the same for all,” Chan, who is also an adjunct professor at the University of California, San Francisco, told Healio. “Now, with the advances of molecular genetics and genomic-guided therapy, we have been able to personalize the treatment of ovarian cancer. Not only based on the different drugs used, with respect to chemotherapy, but also the application of genomics, diagnostics of a patient’s genetic history or genetic signature from their germline, and cancer genetics. So, we’re able to use the advances of the Human Genome Project to guide genetic based treatments with biologic agents.”

DNA repair toolbox

Approximately 25% of ovarian cancer is a result of an inherited autosomal dominant genetic defect in the BRCA gene that demonstrates an inability to correct double-stranded breaks in DNA, according to Chan.

“When you have single-stranded breaks from chemotherapy treatment of ovarian cancer or from natural division of cancer cells, they are generally repaired by a poly (ADP-ribose) polymerase [PARP] enzyme, like a repair truck along the DNA railroad,” he said.

This discovery, Chan said, has led to a breakthrough in treatment.

“Multiple companies have now capitalized on this genetic advance to identify drugs that can inhibit or break down this repair truck," Chan said. "When you break down this repair truck, the cancer cell DNA cannot repair the single-stranded breaks. When it cannot repair the single-stranded breaks, it ultimately leads to double-stranded breaks.”

Because patients with these BRCA mutations are unable to sufficiently repair double-stranded breaks, the cancer cell dies, Chan said.

“Genomic studies and discoveries have been able to really help clinicians identify those patients who can have access to these new drugs that have a particular benefit or significant activity targeted at BRCA or homologous recombination deficiency-associated tumors,” he said. “That's why ovarian cancers have had a just a great response.”

‘Explosion’ of approvals

“One of the most exciting things that I have seen in my career over the last 25 years in taking care of ovarian cancer patients is the explosion of FDA-approved drugs,” Chan said.

There have been approximately 12 new indications over the last 3 to 4 years for the use of novel biologics, including anti-vascular therapies, PARP inhibitors and other immunotherapies, according to Chan.

The FDA in 2018 approved the PARP inhibitors olaparib (Lynparza, AstraZeneca) and rucaparib (Rubraca, Clovis Oncology), as well as the blood vessel growth inhibitor bevacizumab (Avastin, Genentech).

The FDA granted rucaparib accelerated approval as monotherapy for women with BRCA-associated ovarian cancer who had received two or more prior chemotherapies in 2016.

Another PARP inhibitor, niraparib (Zejula, Tesaro), was approved in 2017 for the treatment of recurrent epithelial ovarian cancer, and other gynecologic cancers.

“Over the last couple of months, PARP inhibitors have been incorporated in the upfront treatment of ovarian cancer and that has made a significant impact,” he said. “That’s all based on the genomics of the patient’s germline and also the tumor-based diagnostics.”

Failed treatment option

Although there have been tremendous developments in the treatment of ovarian cancer, not all options have been proven to be effective.

Avelumab (Bavencio; EMD Serono, Pfizer) — a human anti-PD-L1 antibody — which is approved for adults and children aged 12 years or older with metastatic Merkel cell carcinoma, has been shown to be ineffective in the treatment of women with previously untreated advanced ovarian cancer.

JAVELIN Ovarian 100, a phase 3 trial designed to evaluate avelumab, compared three treatment regimens: carboplatin/paclitaxel followed by observation; carboplatin/paclitaxel followed by avelumab maintenance; and avelumab plus carboplatin/paclitaxel followed by avelumab maintenance.

Topline results showed no PFS benefit in either of the avelumab groups, prompting the decision to discontinue the trial.

Surgical approaches

In addition to pharmacologic treatment, surgical techniques have evolved over the last 5 to 10 years, according to Chan. The initial approach for ovarian cancer management involved upfront aggressive surgery with cytoreduction, which means removing as much cancer as possible during the procedure. After the surgery, there is still typically some residual disease that is left behind in areas such as the abdomen and pelvis, according to Chan. That residual disease would then traditionally be treated with chemotherapy.

However, there has recently been a slight shift in the use of chemotherapy and surgery.

“Now, more and more studies have shown that if you give chemotherapy first and then do surgery, the surgery is less invasive and associated with less morbidity, less complication and leads to very good quality of life with comparable survival results,” Chan said.

For instance, results of the phase 3 non-inferiority, randomized, controlled CHORUS trial demonstrated that primary chemotherapy resulted in non-inferior survival outcomes compared with primary surgery in patients with advanced ovarian cancer.

In the CHORUS trial, researchers randomly assigned patients to either undergo primary surgery followed by six cycles of chemotherapy (n = 276) or three cycles of primary chemotherapy followed by surgery and three additional cycles of completion chemotherapy (n = 274).

Patients in the primary surgery cohort and primary chemotherapy cohort demonstrated similar median OS (22.6 months vs. 24.1 months) and a similar 3-year survival rate (32% vs. 34%).

“The paradigm has now slightly shifted from using surgery upfront to using surgery after chemotherapy to reduce some of the tumor so that the surgery is not as complex,” Chan said.

As for whether or not surgery will remain a standard of care in the treatment of ovarian cancer, Chan said he sees it always having a place in the armamentarium, except for certain cases.

“There’s so much volume of disease that I think by removing the disease upfront in certain patients, the ability to get complete cytoreduction, meaning taking out as much cancer as possible, will have a role in ovarian cancer,” he said. “Even with chemotherapy, the ovaries and some of the peritoneal cavity and the extent of disease is such that it’s possible that the blood supply may not be able to access these areas to be able to deliver the chemotherapy as well. Surgery has the ability to resect these areas where it’s hidden from the chemotherapy.”

There are some instances, such as elderly patients, where performing surgery may be too dangerous as a result of other significant comorbidities. Those patients, Chan said, can be treated with primary chemotherapy alone.

Future challenges

Although there has been an emergence of highly effective pharmacologic options that have received FDA approval over the last several years, there are still many challenges that lie ahead in the treatment of ovarian cancer.

“The challenges in the future are, first, we need to find out how to sequence these drugs — not just PARP inhibitors, but the anti-vascular drugs and immunotherapy drugs,” he said. “I think the second challenge is to identify better treatments for the 75% of patients who don’t have BRCA gene mutations. Patients who don’t have this genetic defect will need novel treatment strategies and perhaps personalized therapies with genomic-based treatments. If they don’t have a specific gene defect to target and they’re very heterogeneous with respect to their molecular or tumor characteristics, then I think finding personalized therapies for these patients will be our next goal and our next hurdle.”

Chan said the gynecologic oncology community is envious of other medical oncology colleagues who have had the opportunity to adopt and implement immuno-based therapies into their treatment regimens and have seen significant breakthroughs in cancers such as melanoma and lung cancer.

“We have not yet been able to really capitalize on immunotherapies for our ovarian cancer patients. We are hoping to identify better genetic markers and also molecular genomic characterizations to find better immune-based therapies,” he said. “I think that will be the next clinical trial investigation goal for our field that will hopefully continue to bring better survival for our patients without significantly affecting their quality of life.”