Emerging Frontline and I/O PARP Combination Therapies

Ramez Eskander, MD: The future of therapeutics in ovarian cancer is likely going to incorporate combinatorial approaches. We believe that with single-agent PARP inhibition, we’ve been very successful in the BRCA-mutated population with exciting signals, mostly hypothesis-generating because they were not hypothesis tested in the HRD [homologous recombination deficient] patient population. But the question is how are we going to continue to advance our therapeutic efficacy in patients who may not be biomarker positive here, the BRCA wild type patients or homologous recombination proficient patients, and that may be with combinatorial approaches.

Most recently, in the 2020 SGO [Society of Gynecologic Oncology] annual meeting with abstracts that were released virtually, there were some interesting preliminary results that were reviewed. The OVARIO trial was a single-arm phase 2 study that looked at the combination of bevacizumab plus niraparib, again really focused on the safety data output, which is what was released. The 6-month progression-free survival rate in this patient population was essentially 89%, which is what we would anticipate because these patients are selected on platinum sensitivity prior to transition on to niraparib plus bevacizumab. So this is a well-behaving patient population. Although again the 6-month progression-free survival rate of 89% is exciting, no new safety signal suggesting the combination can be used without unacceptable adverse events to patients being treated with this regimen. So adding to the literature saying combination approaches are safe and there may be utility.

Another trial, GOG-9923, looked at veliparib with an intraperitoneal chemotherapy regimen, and again suggested that this regimen could be administered safely, that there were no concerning signals in the patients enrolled and treated on trial to date. But we can’t make any inferences about therapeutic advantages or benefit based on the data that were released with these abstracts. This is more information about safety.

The future of the care of patients with advanced-stage ovarian cancer is incredibly exciting. This is a very dynamic time, and part of this effort to improve outcomes in these patients is the exploration of novel combinations. Right now we have multiple trials being conducted in parallel, trying to look at the advantage of combining immunotherapy, specifically immune checkpoint inhibitors, with PARP inhibitors, to try to augment response, take tumors that may not be historically immunogenic or respond to immunotherapy, and try to convert them into what we would call hot tumors. So take a tumor from being cold, not responsive to immunotherapy, to hot, responsive to immunotherapy, by looking at these novel combinations.

There are multiple active clinical trials that are either enrolling or have recently completed accrual for which data are not yet mature and have not been released. A couple of these trials will be important to discuss. The first is the IMagyn050 study, which looked at atezolizumab in anti–PD-L1 plus bevacizumab. That was a study that essentially tried to explore whether chemotherapy and the addition of immune checkpoint with antiangiogenic therapy would lead to an improved oncologic outcome. That study has completed accrual, although again the outcome data are not yet mature, and we don’t know if there would be a benefit to the combinatorial approach of immune checkpoint inhibition with anti-angiogenesis therapy. This is really based on previous preclinical data, as well as some of the data from the renal cancer arena.

In parallel, the ATHENA trial was looking at rucaparib with the immune checkpoint inhibitor nivolumab. This is in patients who had systemic therapy for primary disease, who would then receive randomization to 1 of 4 arms, the question being whether the combination of rucaparib plus nivolumab led to an improvement in response rates and oncologic outcomes, again trying to capitalize on the addition of PARP inhibition to try to sensitize the tumor to the immune checkpoint inhibitor. We know that immune checkpoint inhibitors alone, so far in ovarian cancer, the data have not been promising.

The JAVELIN Ovarian 100, where data were once again released at the SGO 2020 virtual meeting, suggested that the hazard ratio with avelumab and maintenance avelumab was 1.43. So our hope is that moving beyond just checkpoint inhibitor with chemotherapy and looking at these novel combinations will lead to better outcomes.

These are not the only trials. There is an additional trial in the front line looking at pembrolizumab in conjunction with olaparib. There is the DUO-O trial, which is again looking at the combinatorial approach with olaparib and new checkpoint inhibitors in patients with advanced-stage ovarian cancer. Essentially, this body of clinical trials has the intent to try to determine whether we can truly identify a patient population who is going to benefit from these approaches and bringing these drugs together.

Now, I would like to point out that JAVELIN Ovarian 100, the translational data that are going to emerge from that trial as we try to understand who may have responded and why, are going to be important in informing future studies and the design of subsequent trials in these patient populations.

Transcript edited for clarity.

Case Overview:

Initial Presentation

• A 68-year-old postmenopausal woman presented with fatigue, urinary frequency, early satiety, abdominal bloating and distention
• PMH: HTN, medically treated with lisinopril
• SH: retired; grandmother of 3; never-smoker; social alcohol use
• PE: abdominal distention, bloating, and a positive fluid wave test; otherwise unremarkable

Clinical work-up

• Pelvic exam with transvaginal ultrasound showed a right ovarian mass
• Chest/abdomen/pelvis CT with contrast revealed a right adnexal 5.3-cm complex mass, a suspicious intraparenchymal liver lesion, retroperitoneal lymph node enlargement and concurrent pleural effusion
• Lymph node and adnexal mass biopsy confirmed high-grade, epithelial ovarian cancer; positive cytology of pleural effusion
  • T1N1M1
• Germline molecular testing showed BRCA1/2 wild-type, HRD+
• CA-125, 438 U/mL
• ECOG: 1

Treatment

• Patient underwent TAH/BSO, lymph node dissection, with suboptimal debulking; residual disease 1.3 cm
• Paclitaxel/carboplatin/bevacizumab + maintenance bevacizumab
  • After 3 cycles, patient underwent second debulking surgery, R0
• Continued on bevacizumab for 6 more cycles
  • Achieved partial response, post treatment CA-125, 40 U/mL
     

Follow-up

• At 3 months
  • CA-125, 18 U/mL
  • Chest/abdomen/pelvis CT showed no gross pelvic masses or nodes
  • Pelvic exam was unremarkable