Pfizer may be the last major oncology player to put a wager on a PARP inhibitor in prostate cancer, but the New York pharma appears to have a winning regimen, partly thanks to its Astellas-partnered stalwart Xtandi.
In patients with newly diagnosed metastatic castration-resistant prostate cancer (mCRPC), adding Pfizer’s Talzenna to Xtandi slashed the risk of tumor progression or death by 37% compared with Xtandi alone. The results came from the phase 3 TALAPRO-2 trial and were shared at the American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU).
The FDA has granted priority review to Pfizer’s application for Talzenna and Xtandi in this mCRPC indication, with a decision now expected this year. And Pfizer is already talking up Talzenna’s blockbuster potential in prostate cancer.
The positive data put Talzenna in position to potentially compete with two other more popular PARP inhibitors in AstraZeneca and Merck’s Lynparza and GSK’s Zejula. For the prostate cancer use, Zejula is in Johnson & Johnson’s custody.
Still, Talzenna’s success in mCRPC may not be solely dependent on Talzenna itself, but instead bolstered by its therapeutic partner Xtandi, a current top seller in prostate cancer.
Drugmakers started combining PARP inhibitors with androgen receptor inhibitors in prostate cancer based on early findings with Xtandi, Chris Boshoff, M.D., Ph.D., Pfizer’s chief development officer for oncology and rare diseases programs, explained in an interview. The drug’s mechanism of directly inhibiting the androgen receptor can elicit additional cancer-killing effects in this type of combination, he said.
A prostate cancer showdown
But even before Talzenna’s positive readout, Lynparza and Zejula had delivered their own phase 3 mCRPC trial wins—both in combination with J&J’s Zytiga. For Lynparza, its Zytiga pairing performed 34% better than Zytiga alone at staving off disease progression or death, according to data from the PROpel trial shared at last year's ASCO GU meeting.
Zejula looks to be the underdog in this indication. In a phase 3 trial dubbed Magnitude, the Zejula-Zytiga pairing only beat Zytiga by 27% on the progression-free survival metric—and that result was only in patients with mutations in their homologous recombination repair (HRR) genes, a subgroup of patients who typically respond better to PARP inhibitors.
By comparison, both Talzenna’s and Lynparza’s wins cover mCRPC patients regardless of HRR mutation status. For Talzenna, its progression or death risk reduction reached 54% in the HRR-deficient group and 30% for those with non-HRR-mutant cancer or unknown status.
With those results, the real competition could come down to Talzenna versus Lynparza. While the two drugs’ risk reduction numbers are quite similar in their own trials, Talzenna appears to have better data because patients in that drug’s trial lived longer at median without their disease progressing.
In AstraZeneca and Merck’s PROpel, patients who received the Lynparza combo went a median 24.8 months without tumor progression.
Conversely, in the current TALAPRO-2 trial, the Talzenna arm hasn’t reached its median progression-free survival threshold. But the existing data suggest that median time will be longer than 28 months and potentially significantly longer, Boshoff pointed out.
That doesn’t mean Pfizer will easily win the PARP game in mCRPC. Thanks to its ovarian cancer market share leadership and broad label, Lynparza is currently the best-selling PARP inhibitor. And it already has a foot in the prostate cancer game, thanks to a 2020 FDA approval in previously treated, HRR-mutated mCRPC. Talzenna, by comparison, only has a small BRCA-mutated, HER2-negative breast cancer indication.
Based on the PROpel study, European regulators in December approved Lynparza, used together with Zytiga, for mCRPC patients who aren’t meant to receive chemotherapy. But the FDA recently pushed back its decision date on the application by three months to conduct a full review.
Uncertain long-term outcomes
Overall survival data from Talzenna’s TALAPRO-2 trial remain immature as 31% of patients had died at the interim analysis. The Talzenna-Xtandi regimen is currently linked to an 11% reduction in death compared with Xtandi alone, but it’s still too early to tell which arm will eventually come out as the winner.
Pfizer expects to have updated overall survival data in the next 12 months, Boshoff said. Before then, the Pfizer exec pointed to other trial analyses—such as delayed time to chemotherapy use—as additional evidence supporting Talzenna’s case.
Besides mCRPC, Pfizer and Astellas are testing Talzenna with Xtandi earlier in the treatment sequence in men with HRR-mutated metastatic hormone-sensitive prostate cancer. That phase 3 TALAPRO-3 trial is expected to read out in the fourth quarter of 2024, Boshoff said. The cancer development exec said he is very confident in the trial’s success because it only selects the HRR-mutated patient population.
Meanwhile, also at ASCO GU, AstraZeneca and Merck presented the final overall survival analysis from PROpel. As nearly half of the trial population had died, the Lynparza-Zytiga combo cut the risk of death by 19%, which wasn’t statistically significant. Although the death risk favored the combo across patient subgroups, the benefit was, as expected, most pronounced in those with BRCA mutations. For the majority of patients who didn't have BRCA abnormalities, the death risk reduction was only 9%.