Moving Toward Personalized Medicine, Immunotherapy Gains Foothold in Ovarian Cancer

Shannon N. Westin, MD, MPH

For more than 30 years after cisplatin received its first approval from the FDA in 1978, platinum-based therapies remained the only treatment for ovarian cancer. That era ended in 2014 with the introduction of the VEGF inhibitor bevacizumab (Avastin) and the PARP inhibitor olaparib (Lynparza), both of which have amassed impressive numbers of FDA approvals in the ensuing years. This is an exciting time in the ovarian cancer space as the use of approved agents are being refined. With multiple treatment options available, clinicians will have to sort through myriad research findings to apply their best clinical judgment in treating each individual patient.

More Indications for PARP Inhibitors

Olaparib

In May, FDA approval for maintenance treatment of ovarian cancer was granted to the combination of olaparib with bevacizumab based on findings from the PAOLA-1 trial (NCT02477644).¹ In the phase 3 trial, investigators compared maintenance olaparib plus bevacizumab to bevacizumab alone in patients with newly diagnosed, advanced ovarian cancer following response to first-line platinum-based chemotherapy combined with bevacizumab, regardless of BRCA mutation status.²

Patients were randomized 2:1 to receive 300-mg olaparib tablets (n = 537) or placebo (n = 269) for up to 24 months. All 806 patients received bevacizumab at 15 mg/kg every 3 weeks for up to 15 months total. The primary end point was the time from randomization until investigator-assessed disease progression or death. With a median follow-up of 22.9 months, there was a statistically significant improvement in median progression-free survival (PFS), at 22.1 months for the combined regimen and 16.6 months for the placebo group (HR, 0.59; 95% CI, 0.49-0.72; P < .001).

In patients with tumors positive for homologous recombination deficiency (HRD), including those with BRCA-mutant tumors, the hazard ratio for disease progression or death was 0.33 (95% CI, 0.25-0.45). In patients with HRD-positive tumors that did not have BRCA mutations, the hazard ratio for disease progression or death was 0.43 (95% CI, 0.28-0.66). These findings led the investigators to conclude that the addition of maintenance olaparib provided a significant PFS benefit to patients with advanced ovarian cancer receiving first-line standard therapy that included bevacizumab, especially for patients with HRD-positive tumors (TABLE).²

“Given that the estimated median PFS in the subgroup of patients with HRD-positive tumors was 37.2 months in the olaparib-with-bevacizumab arm and 17.7 months in the placebo-plus-bevacizumab arm, these are impressive results,” Bradley Monk, MD, US Oncology medical director of gynecologic oncology research and a professor at the University of Arizona College of Medicine–Phoenix, said in an interview with Targeted Therapies in Oncology.

Potential synergy between PARP inhibitors and antiangiogenics has been the motivation behind exploring the use of olaparib with other novel agents. Results from one such pairing, olaparib with the investigational VEGFR inhibitor cediranib (AZD2171), were presented at the American Society of Clinical Oncology 2020 (ASCO 2020) Virtual Scientific Program.

Investigators designed the phase 3 NRG-GY004 trial (NCT02446600) to expand on earlier phase 2 findings that the combination of cediranib and olaparib improved PFS over olaparib alone for patients with platinum-sensitive, high-grade serous/endometrioid ovarian cancer, regardless of BRCA mutation status. This is the first phase 3 trial to compare an all-oral nonplatinum regimen to platinum-based chemotherapy in patients with platinum-sensitive ovarian cancer.

Patients (n = 565) were randomized 1:1:1 to receive either a carboplatin-based doublet regimen, daily cediranib plus twice-daily olaparib, or olaparib 300 mg twice daily. After a median follow-up of 29.1 months, objective response rates (ORRs) were 71.3% for carboplatin doublet, 69.4% for cediranib/olaparib, and 52.4% for olaparib alone, and the combination did not meet the primary end point of PFS improvement. However, comparable clinical activity to standard chemotherapy in the overall population and substantial activity in patients with germline BRCA mutations led the investigators to conclude that the nonplatinum regimen may still have utility in certain patient sets.

According to Shannon N. Westin, MD, MPH, associate professor in the Department of Gynecologic Oncology and Reproductive Medicine at The University of Texas MD Anderson Cancer Center in Houston, the FDA approval of PARP inhibitors during NRG-GY004’s active period has made assessing this trial difficult. “What’s unclear is how much [patients receiving newly approved PARP inhibitors in an NRG-GY004 protocol violation] might have impacted the progression-free survival and overall benefit,” she said. “This trial wasn’t designed to show noninferiority or equivalence, so you have to be cautious. [The results don’t] mean there was an obvious lack of benefit from the nonplatinum drugs; they just didn’t do better.”

Niraparib In another noteworthy development in the PARP inhibitor space, niraparib (Zejula) received FDA approval in April for use as a single agent in first-line maintenance in patients with advanced ovarian cancer. Findings from the phase 3 PRIMA trial (NCT02655016) served as the basis of this designation.⁴

Patients with newly diagnosed advanced ovarian cancer who had responded to first-line platinum-based chemotherapy were randomized 2:1 to receive niraparib or placebo once daily. The primary end point was PFS, in both the overall population and patients who had HRD-positive tumors.⁵

Slightly more than half of the 733 patients in the trial population had tumors with HRD. Within this HRDpositive subgroup, patients randomized to receive niraparib experienced a median PFS of 21.9 months compared with 10.4 months for the placebo group (HR, 0.43; 95% CI, 0.31-0.59; P < .001). In the overall trial population, patients in the niraparib group had a median PFS of 13.8 months versus 8.2 months for those in the placebo group (HR, 0.62; 95% CI, 0.50-0.76; P < .001). Positive results in both the overall cohort and the HRD-positive subgroup led the investigators to conclude that niraparib extended PFS among patients with advanced ovarian cancer regardless of HRD status.

Monk, who was senior author of the trial report, noted that the FDA single-agent frontline approval—when compared against the study’s start date—occurred at a pace he calls “unprecedented.”

Overcoming Barriers of Immunotherapy

Recent clinical trials examining immunotherapeutics have shown promise in the treatment of what was once considered an “immunologically cold” tumor type.

Final results from the KEYNOTE-100 trial (NCT02674061) were presented at ASCO 2020.6 An interim analysis of trial data had found that monotherapy with pembrolizumab (Keytruda) showed modest clinical activity in patients with recurrent advanced ovarian cancer after a median follow-up of 16.9 months; the ORR was 8.0% in all patients and did not show a clear correlation with the number of prior lines of therapy.⁷

The trial included 376 patients divided into 2 cohorts: cohort A (n = 285) had received 2 or fewer prior chemotherapy lines for recurrent ovarian cancer and had been treatment free for 3 to 12 months. Patients in cohort B (n = 91) had received 3 to 5 prior lines of chemotherapy and had been treatment free for at least 3 months. Patients received pembrolizumab 200 mg every 3 weeks for 2 years, with ORR as the primary end point.

At the final analysis, the median follow-up had increased to 37.8 months. The ORR for both cohorts combined was 8.5%. In cohort A, the ORR was 8.1% versus 9.9% in cohort B. Additionally, patient outcomes were analyzed by tumor PD-L1 expression level. “There appeared to be a trend toward increased ORR with higher PD-L1 expression in both cohorts,” Ursula A. Matulonis, MD, who is chief of the Division of Gynecologic Oncology at the Susan F. Smith Center for Women’s Cancers at the Dana-Farber Cancer Institute and a professor of medicine at Harvard Medical School, both in Boston, Massachusetts, said during her presentation of the data. “Median OS [overall survival] was 18.7 months, with a trend toward a longer OS with increasing PD-L1 expression in both cohorts.”

Westin noted that the ORR was comparable to that seen with chemotherapy. “Pembrolizumab is not the home run [in ovarian cancer] that we see in bladder or lung cancer, but KEYNOTE-100 shows that, if your patient benefits from immunotherapy, it’s a durable benefit. This study also shows a strong benefit in clear cell ovarian cancer, which tends to be very chemoresistant, so this response was impressive.”

One of Westin’s own immunotherapy studies has garnered attention following presentation of its results at the 2020 American Association for Cancer Research Virtual Annual Meeting I. The phase 2 trial examined the safety of durvalumab (Imfinzi) combined with chemotherapy in patients with newly diagnosed advanced ovarian cancer (NCT02726997).⁸

The study enrolled 18 patients with untreated, stage III or IV ovarian cancer. The study regimen consisted of a baseline tissue biopsy, followed by durvalumab at 750 mg every 2 weeks, weekly paclitaxel at 80 mg/m², and AUC 6 dosing of carboplatin every 3 weeks.

After a median follow-up of 13 months, median OS was not reached. At 18 months, the OS rate was 69%. The median PFS was 14.5 months, and almost half the patients experienced disease progression.

Westin and colleagues obtained 55 tumor specimens from 9 patients before and after treatment. Among 211 proteins identified, 13 were determined to show differential expression between pre- and posttreatment tissues. A press release from MD Anderson Cancer Center noted that the authors had discovered 1 downregulated protein, XBP1, and 12 upregulated proteins, including PAR, ARID1A, and STING.⁹

“We’re hoping this translational work can help us guide combination therapy because so far trials have shown that the addition of a checkpoint inhibitor to chemotherapy didn’t improve progression-free survival,” Westin says. “What we’re trying to do is move toward more personalized precision medicine based on what actually happens inside the tumor.”

Another eagerly watched immunotherapy trial that was presented at ASCO 2020 involves the use of Vigil in combination with atezolizumab (Tecentriq) in patients with recurrent ovarian cancer (NCT03073525).10 According to Monk, who was an author on the trial report, Vigil is a personalized precision vaccine “constructed from autologous tumor tissue transfected with a DNA plasmid encoding GM-CSF and bi-shRNA- furin, thereby creating TGFβ expression control and enhancing immune activation.”

The trial is a randomized, 3-part, phase 1 safety study of the Vigil vaccine in combination with atezolizumab in patients with recurrent ovarian cancer. Part 2 of the trial is a randomized crossover study in which patients start with 2 cycles of either the vaccine (1 × 10⁶ or 1 × 10⁷ cells/ mL) or atezolizumab (1200 mg) before taking the combined regimen.

According to preliminary results for 21 patients in part 2, median OS was not reached in the Vigil-first group versus 10.8 months in the atezolizumab-first group. A subset analysis of patients with wild-type BRCA1/2 demonstrated a more signifi cant OS benefi t for the 7 Vigil-first patients, with median OS not reached versus 5.2 months (HR, 0.12; 1-sided P = .015) for the 7 atezolizumab-first patients. Initial toxicity reports favored the Vigil-first cohort, with only 3% of patients developing grade 3/4 toxicities compared with 17% of the atezolizumab-first group. The investigators concluded that the combination of Vigil plus atezolizumab is safe, with trial data suggesting lower toxicity and a significant OS advantage in patients with recurrent BRCA1/2 wild-type ovarian cancer treated with Vigil first, followed by the combined regimen.

Exploring Gene Therapy

Gene therapy with the investigational agent VB-111 (ofranergene obadenovec) has also garnered widespread interest among clinicians and investigators alike. VB-111 is a targeted anticancer gene therapy designed for a variety of solid tumors. It has a dual mechanism: a broad antiangiogenic effect and the induction of a tumor-directed viral immune response. Investigators presented interim findings from the OVAL trial (NCT03398655) at ASCO 2020.¹¹

The phase 3 study randomized patients with heavily pretreated recurrent platinum-resistant epithelial ovarian cancer 1:1 to receive VB-111 (1 × 10¹³ viral particles) or placebo, both with weekly paclitaxel at 80 mg/m²). Patients were stratified by the number of prior treatment lines, prior antiangiogenic therapy, and platinum-refractory disease status.

"What we’re trying to do is move toward more personalized precision medicine based on what actually happens inside the tumor." – Shannon N. Westin, MD, MPH

OVAL’s primary end points were OS, safety, and tolerability. The planned total enrollment was 400 patients; currently, 80 patients have been enrolled in the United States and Israel, with enrollment expansion to Europe planned for 2020. In late March, an independent panel determined that the VB-111 arm met the interim prespecified benchmark of a CA-125 ORR at least 10% higher compared with paclitaxel-alone. In the first 60 evaluable randomized patients, the CA-125 cumulative response rate was 53%. These results led the review panel to conclude that the trial should continue without protocol revisions.

Antibody-Drug Conjugates

Antibody-drug conjugates (ADCs) in ovarian cancer are being watched with interest due to the phase 1b/2 FORWARD II trial (NCT02606305), for which interim results for 1 cohort were presented at ASCO 2020.12 In the ongoing study, patients with folate receptor alpha (FRα)-positive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancers are treated with the FRα/tubulin-targeting ADC mirvetuximab soravtansine in combination with bevacizumab, carboplatin, pegylated liposomal doxorubicin, or pembrolizumab. In addition, a triplet of mirvetuximab plus carboplatin and bevacizumab is being tested in patients with FRα-positive platinum-sensitive ovarian cancer.^12,13

Preliminary data were presented for the mirvetuximab soravtansine/bevacizumab cohort, which enrolled 60 patients with FRα-positive, platinum-agnostic, recurrent ovarian cancer with a median 2 prior lines of therapy. In the overall patient population, objective responses were seen in 26 patients, for a confirmed ORR of 43% (95% CI, 31%-57%). In 33 patients with high FRα expression, the confirmed ORR was 61% (95% CI, 42%-77%), with an ORR of at least 50% in each of the platinum-resistant and platinum-sensitive subgroups.

Looking Ahead

For his part, Monk predicts that the most immediate potential for clarity for clinicians is likely to come when results are reported for the IMagyn050 trial evaluating the addition of atezolizumab to a bevacizumab/platinum chemotherapy combination in patients with newly diagnosed stage III or IV ovarian, fallopian tube, or primary peritoneal cancer (NCT03038100).

“Adding immunotherapy to chemotherapy is a validated paradigm despite what the trials JAVELIN 100 [NCT02718417] and JAVELIN 200 [NCT02580058] told us,” he said. “This is already a big year in ovarian cancer, and if IMagyn050, which will report in the very near future, [shows] that atezolizumab and bevacizumab [is] impactful, that’ll really be game changing for us.”

As for Westin, she knows that having too many treatment options is a good problem to have. “But now we need to start thinking about how we can use this information to select the right drug for our patient who’s sitting in front of us in the clinic. PARP inhibitors are clearly here to stay, but there’s an opportunity to get better benefit for a certain population,” she says. “We’ll be focusing now on what to do with the patient population with HRD-positive [tumors] to see if some of these combinations will give better benefits than what we see with just PARP inhibitors alone. It will become increasingly important to test patients’ tumors so we can make the right choice as new therapies and combinations become available.”

_References:

_{1. FDA approves olaparib plus bevacizumab as maintenance treatment for ovarian, fallopian tube, or primary peritoneal cancers. FDA. May 8, 2020. Accessed July 7, 2020. bit.ly/2O5iw9K}

_{2. Ray‑Coquard I, Pautier P, Pignata S, et al; PAOLA-1 Investigators. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N Engl J Med. 2019;381(25):2416-2428. doi:10.1056/NEJMoa1911361}

_{3. Liu JF, Brady MF, Matulonis UA, et al. A phase III study comparing single-agent olaparib or the combination of cediranib and olaparib to standard platinum-based chemotherapy in recurrent platinum-sensitive ovarian cancer. J Clin Oncol. 2020;38(suppl 15):6003. doi:10.1200/JCO.2020.38.15_suppl.6003}

_{4. FDA approves niraparib for first-line maintenance of advanced ovarian cancer. FDA. April 29, 2020. Accessed July 7, 2020. bit.ly/3gCtiR6}

_{5. González‑Martín A, Pothuri B, Vergote I, et al; PRIMA/ENGOT-OV26/GOG-3012 Investigators. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2019;381(25):2391-2402. doi:10.1056/NEJMoa1910962}

_{6. Matulonis UA, Shapira R, Santin A, et al. Final results from the KEYNOTE-100 trial of pembrolizumab in patients with advanced recurrent ovarian cancer. J Clin Oncol. 2020;38(suppl 15):6005. doi:10.1200/JCO.2020.38.15_suppl.6005}

_{7. Matulonis UA, Shapira R, Santin A, et al. Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: Interim results from the phase 2 KEYNOTE-100 study. J Clin Oncol. 2018;36(suppl 15):5511. doi:10.1200/JCO.2018.36.15_suppl.5511}

_{8. Westin SN, Lee S, Zhao L, et al. Pharmacodynamic changes by durvalumab in combination with chemotherapy in women with untreated, advanced stage ovarian cancer. Presented at: 2020 American Association for Cancer Research Virtual Annual Meeting I; June 22-24, 2020. Abstract CT188.}

_{9. Kimmons L. AACR: ovarian cancer clinical trial shows effects, safety of upfront immunotherapy and chemotherapy for advanced disease. MD Anderson Cancer Center. April 27, 2020. Accessed July 7, 2020. bit.ly/2BMBsHM}

_{10. Rocconi RP, Stevens EE, Bottsford-Miller JN, et al. A phase I combination study of vigil and atezolizumab in recurrent/refractory advanced-stage ovarian cancer: Efficacy assessment in BRCA1/2-wt patients. J Clin Oncol. 2020;38(suppl 15):3002. doi:10.1200/JCO.2020.38.15_suppl.3002}

_{11. Arend RC, Monk BJ, Burger RA, et al. Clinical trial in progress: pivotal study of VB-111 combined with paclitaxel versus paclitaxel for treatment of platinum-resistant ovarian cancer (OVAL, VB-111-701/GOG-3018). J Clin Oncol. 2020;38(suppl 15):TPS6097.doi:10.1200/JCO.2020.38.15_suppl.TPS6097}

_{12. Gilbert L, Oaknin A, Matulonis UA, et al. Mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients (pts) with platinum-agnostic ovarian cancer. J Clin Oncol. 2020;38(suppl 15):6004. doi:10.1200/JCO.2020.38.15_suppl.6004}

_{13. ImmunoGen announces initial data from FORWARD II study evaluating mirvetuximab soravtansine in combination with Avastin® in recurrent ovarian cancer, regardless of platinum status. News release. ImmunoGen. May 13, 2020. Accessed July 7, 2020. bit.ly/2BMoBFu}