Pfizer reignites the Parp biomarker debate
Talzenna scores in first-line prostate cancer irrespective of HRR status, but for now we only have Pfizer’s word for it.
While Clovis and Astrazeneca/Merck & Co skirmish over their respective Parp inhibitors’ use in late-line prostate cancer Pfizer yesterday made a bolder claim. Its somewhat forgotten, fourth-to-market Parp inhibitor, Talzenna, was said to have scored in a pivotal study in front-line prostate cancer “with or without HRR gene mutations”.
That last bit is important: Astra/Merck are gunning for an all-comers front-line label for Lynparza – an idea slated by a renowned prostate cancer expert. Johnson & Johnson is pursuing an HRR mutation-restricted indication for Zejula, which failed in non-HRR disease. However, until full Talzenna data are presented the exact benefit will remain an open question.
For now all investors and doctors have is a press release toplining the phase 3 Talapro-2 trial, in which Talzenna plus Xtandi were compared against Xtandi alone in castration-resistant prostate cancer naive to systemic treatment.
Patients had been stratified on entry into Talapro-2 according to whether or not their tumours had DNA damage response (DDR) alteration, such as HRR mutations, and the primary endpoint of radiographic progression-free survival was tested in all those enrolled and in those with DDR deficiencies.
Pfizer said the improvement in rPFS versus Xtandi alone was statistically significant and clinically meaningful. The only numerical data given state that risk of progression was cut by over 30% (exceeding a predefined hazard ratio of 0.696), but it is unclear whether this was the case for both stratification cohorts.
The full data are being held back for a medical conference, and next February’s Asco-GU symposium looks possible.
It was at Asco-GU 2022 that the first pivotal data for Parp inhibitors in front-line prostate cancer were reported, from Lynparza’s Propel and Zejula’s Magnitude studies testing the drugs in combination with Zytiga. While Lynparza scored in patients irrespective of HRR mutation status, this benefit was clearly driven by HRR-positives.
The discussant, University of British Columbia’s Dr Celestia Higano, poured cold water on the biomarker-agnostic claim, saying Lynparza should not be used in all-comers in the absence of overall survival data, and urging more work to understand which patients benefit most.
Undeterred, Astra/Merck later filed Lynparza with the FDA for front-line use irrespective of HRR status.
For its part J&J, which licensed GSK’s Zejula for prostate cancer, presented data from Magnitude showing an effect only in HRR-positive patients, and it is in these that Zejula is now awaiting EU approval. The difference in terms of market potential is significant: only 25-30% of front-line metastatic castration-resistant prostate cancer patients are thought to harbour HRR mutations.
Interestingly, J&J has said nothing about whether Zejula has been submitted to the FDA in prostate cancer, either in front or later-line use.
|Cross-trial analysis of Parp inhibitors in 1st-line prostate cancer
|Lynparza (Astrazeneca/ Merck & Co)
|Zytiga combo vs Zytiga
|Zytiga combo vs Zytiga
|Xtandi combo vs Xtandi
|Xtandi combo vs Xtandi
|All-comers (stratified for DNA repair gene defect)
|All-comers (stratified for DNA repair gene defect & prior agent)
|NE vs 13.9mth (HR=0.50)
|19.0mth vs 13.9mth (HR=0.64)
|Efficacy shown "with or without HRR gene mutations"
|24.1mth vs 19.0mth (HR=0.76)
|~8mth** vs ~10mth** (HR=1.09)
|HRR + non-HRR
|24.8mth vs 16.6mth (HR=0.66)
|NEJM, Jun 2022
|Asco-GU, Feb 2022
|Pfizer PR, Oct 2022
|Filed in US in all-comers (Q4 Pdufa)
|Filed in EU for HRR+ (no info on US filing)
|Data "being shared with global regulators"
|Reads out Mar 2023
|Note: all data are rPFS (radiographic progression-free survival), for comparability given by investigator assessment; *allowed Zytiga ≤4wk; **Evaluate Vantage read off the K-M curve; ADT=androgen deprivation therapy.
While ovarian cancer is the big battleground for Parp inhibitors, Lynparza is also approved in second-line, HRR-positive prostate cancer. A fourth Parp, Clovis’s Rubraca, carries a third-line prostate cancer label under accelerated approval, and this week reported positive data from a confirmatory study.
Clovis’s own first-line trial, Caspar, combines Rubraca with Xtandi, but does not read out until next year, according to clinicaltrials.gov.
For Pfizer to make good on its claim the full Talapro-2 data have to show clinically meaningful benefits in non-HRR patients, with at least nominal statistical significance, and not just in patients irrespective of HRR status. It goes without saying that safety, an important consideration for Parp inhibitors, will also be scrutinised.
The bull case for Pfizer is that Talzenna shows a strong benefit in HRR-negatives, and that the FDA limits Lynparza use to HRR-positive disease. Astra/Merck have a fourth-quarter Pdufa date, so the second question will be answered soon enough.