- In Phase 2 trials, Tesaro Inc.'s PARP inhibitor Zejula, paired with Merck & Co.'s Keytruda to treat patients with recurrent, platinum-resistant ovarian cancer, demonstrated just a small benefit in platinum-refractory non-BRCA positive patients, and no benefit in platinum-resistant patients with a BRCA mutation.
- While the company said preliminary results from the TOPACIO trial suggest the combination of Zejula and an anti-PD-1 antibody could provide meaningful clinical benefit, some Wall Street analysts were unconvinced. Cowen & Co. analysts said the observed lack of effect in platinum-resistant BRCA-positive patients and the "lack of correlation between BRCA status and response rates raises concerns about this dataset."
- The pairing with Keytruda is especially interesting because it is similar to the PARP/checkpoint inhibitor combination that AstraZeneca plc and Merck are currently developing with Lynparza and Keytruda. Competition in this space is sure to heat up even more as AstraZeneca's rivals look to add more indications to their respective PARP therapies.
Editor's Note: This story was updated from its original version to better reflect the TOPACIO results and correct the patient population that Zejula is approved for.
It's been a full year since the Food and Drug Administration approved Zejula (niraparib), a poly(ADP-ribose) polymerase (PARP) inhibitor indicated as a maintenance therapy for adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.
Tesaro's latest data show that combining the PARP inhibitor with Keytruda (pembrolizumab) produced overall response rates (ORR) of 29% in patients with platinum-resistant/refractory ovarian cancer with a tumor BRCA mutation, similar to those achieved in the BRCA-mutant platinum-resistant population through PARP inhibition alone (25-30%). However, for patients with platinum-refractory ovarian cancer with a tumor BRCA mutation, historical response to PARP inhibitors alone is 0% to 14%.
The TOPACIO data indicate an ORR of 26% in patients with platinum-resistant/refractory ovarian cancer without a tumor BRCA mutation and historical response to PARP inhibitors alone is 5% to 10% for those platinum-resistant patients without the mutation.
Cowen analysts pointed out that the 27% ORR for chemotherapy (paclitaxel, PLD, topotecan) in combination with Avastin (bevacizumab) was also in line with the ORR from administration of Zejula plus Keytruda.
Despite lukewarm study results, Tesaro plans to charge ahead with its next PARP-based trial, which will examine Zejula in combination with the biotech's own in-house anti-PD-1, TSR-042. The planned trials after that will look at cohorts pairing carboplatin-pacitaxel with TSR-042; Zejula and Avastin (bevacizumab) with TSR-042; and carboplatin-pacitaxel and Avastin with TSR-042.
In 2017, Tesaro had a difficult time enrolling patients into its BRAVO study, thought to be due to broad availability of other PARP inhibitors. And in the TOPACIO study, the trial began with 121 participants, but the company only reported on the results from approximately 60 "evaluable" patients in Monday's announcement.
Why was this? Tesaro representative Kate Rauch explained that while TOPACIO was a Phase 1/2 clinical trial designed to evaluate the safety and efficacy of Zejula plus Keytruda in patients with recurrent, platinum-resistant ovarian cancer or triple negative breast cancer, the data presented yesterday at the 2018 Society for Gynecologic Oncology (SGO) Annual Meeting on Women's Cancer were "from the group of patients with ovarian cancer and did not include the group of patients with triple-negative breast cancer."
Meanwhile, PARP market leader Lynparza (olaparib), with its three approved indications, brought in $297 million in sales in 2017; Clovis Oncology Inc.'s Rubraca (rucaparib) raked in $55.5 million that same year; and Zejula made $109 million in its first nine months on the market. Tesaro predicted in a corporate presentation that Zejula will have full-year sales of $255–275 million in 2018.
The company also said the combined U.S. and EU market opportunity for Zejula in ovarian cancer is $4 billion, with $1.4 billion of that linked to Zejula's sole approved indication, and an estimated $2.6 billion attributed to the anticipated approval of Zejula as a first-line treatment for ovarian cancer.
At the SGO meeting, Tesaro also discussed results from a retrospective analysis of a Phase 3 study of Zejula. The analysis found that two baseline characteristics, body weight and platelet count, were "significant factors" relating to whether a patient developed Grade 3 or 4 thrombocytopenia when taking Zejula.
Abstracts containing additional data from the TOPACIO trial, including results from patients with platinum-resistant ovarian cancer and patients with triple-negative breast cancer, have been submitted to another upcoming medical meeting.