Clinical Data From the Phase III PRIMA trial

Wendel Naumann, MD:The PRIMA trial was really a landmark trial in patients with ovarian cancer in terms of maintenance therapy. We knew from SOLO-1 that PARP [poly ADP ribose polymerase] inhibition was important in patients withBRCAmutations, but this took it a step farther. We now know that PARP inhibition is good for all patients, that all patients benefit from this. We do know that there are gradations based on their homologous repair deficiency [HRD]. So if you’re homologous deficient, your benefit from the PARP inhibition is similar those patients withBRCAmutations. Now if you’re proficient, as we discussed, those patients don’t benefit as much, but they still benefit.

The primary end point of the PRIMA trial was progression-free survival [PFS]. It’s very difficult to show an overall survival [OS] in any upfront ovarian cancer trial. So the OS is probably not attainable, particularly outside of theBRCA-mutated population. Do I think that this will increase the survival? I do think it will, but it’s going to be difficult to show this in a clinical trial.

The PRIMA trial and the other trials in ovarian cancer in maintenance therapy have really changed, fundamentally, how we talk to patients about treatment. It used to be we would treat patients with chemotherapy and then there would be no treatment afterward. And now I think it’s the standard of care to at least discuss maintenance therapy, and we must discuss the risks, and the benefits, and the adverse effects of these medications. Now with the HRD testing, we can be a little bit more precise about the benefit that patients will get, and we need to have a very honest discussion about that versus the toxicities of these medicines. There is some nausea that is associated with these medicines. There’s some bone marrow suppression associated with these medicines. But there’s also great benefit. I think we need to do a better job in the future of trying to predict who, particularly in the HR-proficient group, will benefit from PARP inhibition.

The PRIMA trial was designed to take a very high-risk patient population, patients with residual disease. Once they had a response to platinum therapy, they were then randomized. Randomization started at the end of chemotherapy. Patients were put in either placebo or maintenance niraparib and followed for PFS end point.

Niraparib does have adverse effects. These can be chronic. Most patients tolerate this medicine well. I think it’s important to tell patients that they may have adverse effects up front and to expect that, manage these aggressively, whether it’s manage the nausea, manage the sleep disturbances, and we also tell patients that these adverse effects are going to get better over time.

I think it’s important when we first start these medicines, especially in the first couple of months, to make sure that there’s not sudden bone marrow suppression because this is a known adverse effect with these medicines but manageable. And if they have any kind of bone marrow suppression, whether it’s thrombocytopenia, anemia, or even if they have neutropenia, we can stop the medicine, let patients recover, and restart or perhaps dose reduce. Particularly for patients who have low starting platelets or low weight, we need to be careful about the dose, and we may want to start at a lower dose. The recommended dose for patients under 77 kilograms or platelet counts under 150,000 is 200 mg a day as opposed to the 300 mg a day dosing.

I think it’s important to understand that in the PRIMA trial and other trials, dose reduction is not necessarily associated with decreased efficacy. So we don’t think that dose reduction based on adverse effects is going to take away from the efficacy of these drugs.

Transcript edited for clarity.

Case: A 54-Year-Old Female With Ovarian Cancer

H & P

• 54-year-old female presents with abdominal pain and bloating
  • Pathology: High-grade, stage III, epithelial ovarian cancer of the right ovary, and positive for numerous small (<0.7cm) pelvic and para-aortic lymph nodes disease
  • CA-125, 305 U/mL
• Imaging
  • CT with contrast of the pelvis, abdomen, and chest revealed a right adnexal 2.9-cm mass, no ascites or pleural effusion noted
• Treatment
  • Patient underwent exploratory laparotomy with unilateral salpingo-oophorectomy, pelvic and para-aortic lymph node dissection
    • Status post-surgery: macroscopic residual disease (R2), 1.2cm lesion
    • Received second cytoreduction surgery
  • Germline molecular testing showed HRD +,BRAC1alteration
  • Initiated IV/IP paclitaxel/cisplatin
  • Initial post treatment CA 125, 48 U/mL
  • Started on niraparib maintenance therapy
• Follow-up:
  • CA 125, 25 U/mL upon completion of chemotherapy (6 cycles)
  • CT at 2.5 months post-surgery, no gross pelvic masses; chest CT unremarkable
  • Unremarkable pelvic exam
  • ECOG: 0