Moving the Meter on Ovarian Cancer

Michael J. Birrer, MD, PhD

Despite a decrease in the diagnosis of ovarian cancer and in the number of deaths due to the malignancy in the United States over the past 25 years, the disease remains a silent killer that is responsible for approximately 14,000 deaths every year.¹ The 5-year survival rate stands at about 46.2%, significantly lower than the 90% rate for breast cancer, the 80% for endometrial cancer, and the nearly 70% for cervical cancer.^1,2

Yet researchers and clinicians are optimistic these days that they are closer than ever to more effective therapies for this disease. “It’s actually a very exciting time,” said Michael J. Birrer, MD, PhD, in an interview with OncologyLive. He said there was “a very discouraging period of time, from the late 1990s all the way up until 2000 to 2010, with just carbotaxol [for treatment]," referring to the chemotherapy combination of carboplatin and paclitaxel.

“There wasn’t a lot of progress, particularly as we saw progress with other tumors.” But Birrer, a professor of Medicine at Harvard Medical School and director of the Gillette Center for Gynecologic Oncology at Massachusetts General Hospital, said there are many clinical trials in progress now.

He said that the 2 most noteworthy developments in ovarian cancer treatment at this time involve poly(ADP-ribose) polymerases (PARP) inhibitors and antiangiogenesis therapies. Another promising approach is the development of drugs that target the folate receptor.

Both PARP inhibitors and antiangiogenic drugs could form some potent combinations in the future, said Mansoor Raza Mirza, MD, a key researcher in the PARP inhibitor field who is chief oncologist at Righospitalet in Copenhagen, Denmark.

PARP Inhibitors Reshaping the Field

“I hope that now we will have PARP inhibitors, some combinations of PARP inhibitors with other drugs, like antiangiogenic drugs. We’re already doing trials with that,” Mirza said. “We’re really in a very interesting era, and we’re seeing some major gains for our patients.”A flurry of research findings in recent weeks shows how vital PARP inhibitors as an emerging class of agents have become to the development of new treatments for patients with ovarian cancer. The field has blossomed with 1 approved drug and at least 4 other agents undergoing clinical trials.

These drugs take advantage of cellular DNA damage caused by BRCA1 or BRCA2 mutations, blocking PARP enzymes that cancer cells need to repair the damage.2 They can be used as monotherapy in patients with known mutations in DNA repair proteins or as combination therapy with DNA-damaging chemotherapeutic agents or radiotherapy.

Germline BRCA (gBRCA) mutations are believed to be present in 10% to 20% of high-grade ovarian cancers, while somatic alterations in BRCA1/2 and DNA repair defects are evident in an estimated 50% of high-grade tumors, according to the My Cancer Genome database.

The FDA approved the PARP inhibitor olaparib (Lynparza) in 2014 as monotherapy in patients with advanced ovarian cancer with deleterious gBRCA mutations after 3 or more prior lines of chemotherapy. The approval was based on the phase II Study 19, which demonstrated that women taking the drug experienced partial shrinkage or complete disappearance of the tumor, with 34% of participants experiencing an objective response rate on average of 7.9 months.³

A subsequent analysis of that data showed that in patients with platinum-sensitive relapsed serous ovarian cancer, olaparib increased overall survival (OS) when given as maintenance therapy, with the greatest OS advantage in women who had a BRCA mutation (HR, 0.62).⁴ However, the P values were nominal and did not meet the criterion for statistical significance (P <.0095).

In late October, AstraZeneca reported that single-agent olaparib significantly improved progression-free survival (PFS) compared with placebo in the maintenance setting for patients with advanced BRCA-positive ovarian cancer in the phase III SOLO-2 trial.5 Although specific data from the trial are not yet available, Astra- Zeneca said that the median PFS with olaparib was significantly higher than the median 8.4-month PFS reported in the olaparib arm of phase II Study 19 in a similar population.⁵

Niraparib, another PARP inhibitor, also is showing promise as maintenance therapy, demonstrating significantly improved PFS compared with placebo among patients with platinum-sensitive recurrent ovarian cancer regardless of BRCA status.

According to the results of the phase III NOVA trial presented in October 2016, women with germline BRCA mutations who took maintenance niraparib had a median PFS of 21 months, compared with 5.5 months among women who took placebo.⁶ Women without the BRCA mutation also experienced a longer PFS with niraparib: 9.3 months compared with 3.3 months for the women who took a placebo. The FDA granted fast track designation to niraparib based on these findings. “This is going to change our way of thinking about ovarian cancer,” Mirza, lead author of the NOVA trial, said in an interview with OncologyLive.

“When patients with ovarian cancer relapse, we had to tell them that this is a deadly disease, and patients will receive chemotherapy again and again, and eventually die from the disease. We are talking about turning this into a chronic disease, so patients can live with minimal toxicity after treatment, and have a normal life for a very long time.”

“It’s not a small subgroup of patients,” added Mirza. “These are all patients with high-grade endometrial cancer. These are landmark results that will change our practice.”

Serious adverse effects (AEs) of olaparib included the development of myelodysplastic syndrome, acute myeloid leukemia, and lung inflammation.³

For niraparib, the NOVA trial findings showed that more than 10% of patients had grade 3/4 AEs, including thrombocytopenia, anemia, and neutropenia, but they did not cause cessation of therapy in most cases, and were resolved with dose adjustments.⁶

PARP inhibitors are not just for women with BRCA mutations, however. The inhibitors also prevent cancer cells from repairing themselves after they have been damaged by chemotherapy.

“In the non-gBRCA cohort, the whole population, again, benefited in a clinically meaningful way,” Mirza explained. “The patients had a median PFS benefit increase from 3.9 months to 9.3 months. Again, one-third of patients remained on treatment for a long time without progression at the time of data cutoff, showing the durability and efficacy of the drug for these patients.”

Another PARP inhibitor in late-stage development is rucaparib, which the FDA is evaluating under an accelerated approval timeline for the treatment of patients with advanced, BRCA-mutated tumors who have been treated with 2 or more chemotherapies. A decision is expected in February 2017, according to the drug’s manufacturer, Clovis Oncology.

In results reported at the 2016 ESMO Congress, the ORR was 53.8% among 106 patients treated with rucaparib (95% CI, 43.6-63.5). Complete response was confirmed in 9 patients (8.5%), partial response was seen in 48 (45.3%), and stable disease was achieved by 36 patients (34.0%).⁷ Progressive disease occurred in just 9 patients and 4 patients were not evaluable. The median duration of investigator-assessed confirmed response was 9.2 months (95% CI, 6.6-11.7 months).⁷

Veliparib, a PARP inhibitor that AbbVie is developing, is being explored in a phase III trial in women with previously untreated, stage III or IV, highgrade serous, epithelial ovarian, fallopian tube, or primary peritoneal cancer (NCT02470585). The trial, which is seeking to recruit 1100 participants, will evaluate the gBRCA status of patients but is not restricted to those who harbor the mutation.

Strategies for Attacking Angiogenesis

A fifth agent, talazoparib, will be evaluated in a phase II trial that seeks to enroll 500 women with relapsed ovarian cancer (NCT02836028). The study, sponsored by Medivation, Inc, will compare talazoparib monotherapy with the novel agent plus temozolomide. Eligible participants must have a deleterious germline or somatic BRCA1 or BRCA2 mutation, or a high diagnostic homologous recombination deficiency score (myChoice score ≥42), which represents a loss of DNA repair function based on testing performed at a sponsor-approved laboratory.The process of angiogenesis plays an important role in the growth of ovarian cancers, making therapies inhibiting the production and growth of the tumor vasculature an attractive therapeutic target.⁸

Bevacizumab (Avastin), which blocks VEGF, had already been used off-label for ovarian cancer when the FDA approved the drug for the treatment of patients with platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in 2014. The indication calls for the drug to be used in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan.

The approval was based on the AURELIA trial, which Birrer said was the first study that examined the use of bevacizumab with chemotherapy in platinum-resistant ovarian cancer. The median PFS of patients who received bevacizumab plus chemotherapy was 6.8 months (95% CI, 5.6- 7.8) compared with 3.4 months (95% CI, 2.1-3.8) for those who received chemotherapy alone.⁹ Adverse effects of bevacizumab that affected at least 15% of the patients in the AURELIA trial, included neutropenia, peripheral sensory neuropathy, and hypertension. Gastrointestinal perforations were reported in 1.7% of bevacizumab- treated patients.

Antiangiogenic therapies may play another role in cancer treatment, by reversing immunosuppression, which may make it a powerful tool in combination with immunotherapy.

Further results from the GOG0213 trial, reported in 2015, evaluated the use of bevacizumab among women with platinum-sensitive recurrent ovarian cancer.¹⁰ The results showed improvement in overall survival—a first such finding in this population. Although the findings were not statistically significant, women with platinum-sensitive recurrent ovarian cancer who took bevacizumab experienced an overall survival of almost 5 months longer compared with women who took chemotherapy alone.

The use of bevacizumab continues to be promising. “I think combinations with bevacizumab are going to be the new direction, and another hot area of research is trying to identify patients who would benefit the most from the treatment,” said Birrer.

Folate Receptor—Targeted Drugs

In addition to bevacizumab, there are several other antiangiogenesis therapies under study for treatment of ovarian cancer. They include pazopanib as maintenance therapy, nintedanib for chemotherapy- naïve patients, and cediranib in combination with chemotherapy and as maintenance.⁸Yet another promising treatment for ovarian cancer may be folate receptor—targeted drugs.¹¹ The folate receptor had been identified a few years ago as a new molecularly targeted entity. It is highly overexpressed in many solid tumors, including ovarian cancer, in about 95% of serous tumors, Birrer explained, but expressed as much in most other tissues.

Trying to Improve Chemotherapy

One agent poised to move into a phase III trial is mirvetuximab soravtansine (IMGN853), an antibody— drug conjugate that targets folate receptor alpha (FRα). ImmunoGen is planning the phase III FORWARD I trial in which the agent will be evaluated versus physician’s choice of chemotherapy in patients with FRα-positive platinum-resistant ovarian cancer who have previously received up to 3 treatment regimens.¹² The company estimates that 5000 to 7000 patients a year in the United States would meet the criteria.At one point, many in the gynecologic oncology community pinned their hopes on intraperitoneal (IP) chemotherapy as an emerging treatment for ovarian cancer. The premise of bathing the peritoneal cavity with chemotherapy directly to the affected area with high concentration chemotherapy is promising, but study findings are conflicting.

Results presented in March this year at the 2016 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer were disappointing.¹³ The phase III GOG252 trial, which included 1560 patients, found that IP chemotherapy was not any more effective in prolonging survival than intravenous chemotherapy, and it was more difficult for patients to tolerate. There were 3 arms to the study:

• Intravenous carboplatin AUC (area under the curve) 6/intravenous weekly paclitaxel at 80 mg/m²
• Intraperitoneal carboplatin AUC 6/intravenous weekly paclitaxel at 80 mg/m²
• Intravenous paclitaxel at 135 mg/m² on day 1/intraperitoneal cisplatin at 75 mg/m² on day 2/intraperitoneal paclitaxel at 60 mg/ m2 on day 8

All patients also received intravenous bevacizumab (15 mg/kg) with cycles 2 through 6 of chemotherapy, followed by bevacizumab alone for cycles 7 through 22.

These findings surprised many oncologists who were attending the session, as earlier studies had shown IP chemotherapy as beneficial; however, many patients were not able to complete their treatments because of the toxicity.¹³

The regimen for the GOG252 study did include a reduced dose of IP cisplatin, which could have affected its overall efficacy, the presenters noted. However, a study presented at the 2016 ASCO Annual Meeting 3 months later, in June, showed more promising findings with IP chemotherapy.¹⁴ The phase II randomized trial, OV21/ PETROC, included 275 women, most of whom had stage IIIc disease, who had undergone neoadjuvant IV chemotherapy followed by delayed debulking surgery. One arm of the 3-arm study was discontinued. Following surgery, the patients were assigned to either:

• Intravenous paclitaxel (135 mg/m²) and intravenous carboplatin (AUC 5/6) on day 1, followed by intravenous paclitaxel (60 mg/ m2) on day 8, over three 21-day cycles
• Same regimen, but the carboplatin and the paclitaxel on day 8 were delivered via IP The findings of this study showed the progression rate in women who had intravenous chemotherapy alone was 42.2%, but the progression rate was only 18.9% among women who had IP chemotherapy. The regimen was also well tolerated.

Continuing Challenges

The presenter pointed out that the previous study negative study, GOG252, included bevacizumab for all patients, which may have contributed to the poor tolerability of the treatment.There has to be an increased push for all women with ovarian cancer to undergo germline sequencing, say many oncologists. Current practice usually reserves BRCA1 and BRCA2 testing for young women and those with serous tumors, but according to Birrer, 8% to 15% of women with ovarian cancer have no family history of this type of tumor, yet they are found to have BRCA1, BRCA2, PALB2, or some other gene mutation.

“That has huge implications in terms of their prognosis,” he said. “It has huge implications as to whether they should get PARP inhibitors, and it has huge implications on the kids in the family. We’ve been beating this drum for at least 3 years now.”

In addition to the need for broader molecular testing, Birrer sees 2 extremes when discussing the challenges facing ovarian cancer research and treatment. “The holy grail is still an early detection assay for this tumor,” he said. “The vast number of tumors are diagnosed at stage III or IV, at least 75% to 80%. And there has been really minimal progress in developing an early detection assay for ovarian cancer.”

Speaking to Patients

The other extreme is learning why so many tumors become platinum resistant. There is still much work to be done in this area.Although ovarian cancer is difficult to treat because of the late stage of discovery in so many women, Birrer and other oncologists are encouraged. “With surgery and chemotherapy, we can chase away this tumor in probably more than 80% of patients, but most tumors come back and the time it takes them to come back is highly variable,” Birrer said.

And the tumors do recur in between 70% and 75% of women treated for the disease. Patients can live for 3 or more years disease-free, with a high quality of life, and for those who do experience a recurrence, there are now new treatments available that were not available when they were first diagnosed.

“Fifteen, 20 years ago, we would be forced to simply retreat with carboplatin and Taxol,” said Birrer. “We now have a lot of choices to chase away the tumor again. This provides good quality disease-free survival, and time. This is the most exciting time in ovarian cancer that I have ever experienced.”

References

1. SEER Stat Fact Sheets: Ovarian Cancer. National Cancer Institute. Part of the National Institutes of Health. http://seer.cancer.gov/ statfacts/html/ovary.html Accessed October 26, 2016.
2. Underhill C, Toulmonde M, Bonnefoi H. A review of PARP inhibitors: from bench to bedside. Ann Oncol. 2011;22(2):268-79. doi:10.1093/ annonc/mdq322.
3. FDA approves Lynparza to treat advanced ovarian cancer [press release]. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ ucm427554.htm. Published December 19, 2014. Accessed November 1, 2016.
4. Ledermann JA, Harter P, Gourley C, et al. Overall survival (OS) in patients (pts) with platinum-sensitive relapsed serous ovarian cancer (PSR SOC) receiving olaparib maintenance monotherapy: An interim analysis. J Clin Oncol. 2016;34(suppl; abstr 5501).
5. LYNPARZA™ (olaparib) phase III SOLO-2 trial shows significant progression- free survival benefit [press release]. Wilmington, DE: AstraZeneca; October 26, 2016. https://www.astrazeneca-us.com/media/press-releases/ 2016/lynparza-olaparib-phase-III-solo-2-trial-shows-significant- progression-free-survival-benefit-10262016.html.
6. Mirza MR, Monk B, Herrstedt J, et al. Niraparib maintenance therapy in platinum-sensitive recurrent ovarian cancer [published online October 8, 2016]. N Engl J Med. doi: 10.1056/NEJMoa1611310.
7. Kristeleit RS, Shapira-Frommer R, Oaknin A, et al. Clinical activity of the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib in patients ( pts) with high-grade ovarian carcinoma (HGOC) and a BRCA mutation (BRCAmut): Analysis of pooled data from Study 10 ( parts 1, 2a, and 3) and ARIEL2 (parts 1 and 2). Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract 8560.
8. Reinthalle, A. Antiangiogenic therapies in ovarian cancer. Memo. 9;139. doi:10.1007/s12254-016-0282-4.
9. FDA approval for bevacizumab. https://www.cancer.gov/about-cancer/ treatment/drugs/fda-bevacizumab#Anchor-Ovarian. Updated December 4, 2014. Accessed November 2, 2016.
10. Coleman RL, Brady RF, Herzog TJ, et al. A phase III randomized controlled clinical trial of carboplatin and paclitaxel alone or in combination with bevacizumab followed by bevacizumab and secondary cytoreductive surgery in platinum-sensitive, recurrent ovarian, peritoneal primary and fallopian tube cancer. Presented at: Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer 2015; March 28-31, 2015; Chicago, IL. Abstract 3.
11. Assaraf YG, Leamon CP, Reddy JA. The folate receptor as a rational therapeutic target for personalized cancer treatment. Drug Resist Updat. 2014 Oct-Dec;17(4-6):89-95.
12. ImmunoGen reports efficacy and safety data from a 46-patient cohort of mirvetuximab soravtansine in FRα-positive ovarian cancer [press release]. Waltham, MA: ImmunoGen, Inc; May 18, 2016. http://investor. immunogen.com/releasedetail.cfm?releaseid=971713.
13. Walker JL, Brady MF, DiSilvestro PA, et al: A phase III trial of bevacizumab with IV versus IP chemotherapy in ovarian, fallopian tube, and peritoneal carcinoma NCI-supplied agent(s): A GOG/NRG trial (GOG 252). 2016 Society of Gynecologic Oncology Annual Meeting. Late-breaking abstract 6. Presented March 21, 2016.
14. Mackay H, Gallagher CJ, Parulekar WR, et al. OV21/PETROC: a randomized Gynecologic Cancer Intergroup (CGIG) phase II study of intraperitoneal (IP) versus intravenous (IV) chemotherapy following neoadjuvant chemotherapy and optimal debulking surgery in epithelial ovarian cancer (EOC). J Clin Oncol. 2016 (suppl; abstr LBA5503).