Asco-GU – prostate cancer Parps move to the front line

Lynparza squares off against Zejula while Rubraca and Talzenna wait in the wings, but should first-line use be restricted by biomarkers?

Glaxosmithkline/Johnson & Johnson’s Zejula might have found a way to the prostate cancer market at last. Having been abandoned in the third-line setting in 2020 the drug has yielded a positive result in the first-line Magnitude study, according to full data presented at Asco-GU yesterday.

However, it will find itself up against Astrazeneca/Merck & Co’s rival Parp inhibitor Lynparza, which has itself scored a front-line success, courtesy of the Propel trial. The big difference is that Lynparza’s benefit seems independent of patients’ HRR status, while Zejula’s is restricted to HRR-mutated cancer; the need for genetic testing could see the latter relegated to an also-ran.

That is, of course, if the regulator agrees that Lynparza’s effect really does extend beyond HRR-positive disease. Both studies tested the addition of a Parp on top of Zytiga, and a subgroup analysis of HRR-negative patients in Propel presented at Asco-GU did show a numerical radiographic PFS benefit; but the upper bound of its confidence interval was 0.97, meaning that the effect was not far off insignificance.

Do not use?

Discussing the two datasets yesterday, University of British Columbia’s Dr Celestia Higano said Lynparza should not be used in all metastatic castrate-resistant prostate cancer (mCRPC) patients in the absence of overall survival data. She cited “drug and financial toxicity” with the Lynparza plus Zytiga combo, and said more work was needed to understand which patients benefit most.

The difference in terms of market potential is significant: only 25-30% of front-line mCRPC patients harbour HRR mutations, she stated.

If the FDA agrees, this would imply that front-line patients should be tested for HRR status – something that would play hugely to the advantage of Zejula. Though this drug did cut progression risk by 26% in HRR-positives, in non-HRR patients Zytiga monotherapy did numerically better than the combo, which added grade 3/4 toxicity.

Meanwhile, in Propel Astra/Merck were able to boast of an rPFS benefit for Lynparza of 8.2 months in all-comers, translating into a 34% reduction in risk of progression by investigator review (p<0.0001). However, this was clearly driven by HRR-positive patients, who experienced a 50% reduction in risk of progression.

Cross-trial analysis of Parp inhibitors in prostate cancer, by genetic mutation type
  Lynparza (Astrazeneca/Merck & Co) Zejula (Glaxosmithkline/J&J) Rubraca (Clovis)
Supporting trial Profound Propel Magnitude Galahad Triton2
Setting 2L (post Zytiga or Xtandi) 1L 1L (allows Zytiga ≤4wk) 3L (post chemo & ADT) 3L (post chemo & ADT)
Regimen MonoRx vs Zytiga or Xtandi Zytiga combo vs Zytiga Zytiga combo vs Zytiga MonoRx uncontrolled MonoRx uncontrolled
Population in trial HRR mutated All-comers All-comers (with stratification) Brca1/2 or biallelic mutation Brca1/2 or ATM mutated
Any HRR 5.8mth vs 3.5mth (HR=0.49, p<0.0001)* NE vs 13.9 mth (HR=0.50) 19.0mth vs 13.9mth (HR=0.64, p=0.0022) ORR 27% ORR 30%
HRR (Brca1/2) 9.8mth vs 3.0mth (HR=0.22) NA 19.3mth vs 12.4mth (HR=0.50, p=0.0006) ORR 41% ORR 44%*
Non-HRR NA 24.1mth vs 19.0mth (HR=0.76) ~8mth** vs ~10mth** (HR=1.09) NA NA
HRR + non-HRR NA 24.8mth vs 16.6mth (HR=0.66, p<0.0001) NA NA NA
Note: all data are rPFS (radiographic progression-free survival) unless stated; for comparability Propel & Magnitude rPFS figures are given by investigator assessment; *approved use; **Evaluate Vantage estimate; ADT=androgen deprivation therapyORR=objective response rate; NE=not estimable. Source: Esmo 2019, Asco-GU 2022 & product labels.

Dr Higano said Propel’s all-comers median rPFS benefit, around 25 months, was one of the longest she had seen in this setting.

However, comparing the medians in HRR-positive patients across the two trials (not estimable for Propel and 19 months in Magnitude) she stated: “Do not interpret this to mean that [Lynparza] is better than [Zejula]. It does not mean that. It only [shows] the difference in the populations being treated in these trials.”

This goes to the heart of some key differences between Propel and Magnitude. While both were termed first-line trials, the latter did allow prior Zytiga, as long as this had been given within four months of randomisation, while the former did not.

Then there is the issue of Brca1/2-mutated disease, an especially aggressive type of HRR mutation. Magnitude stratified patients to ensure a certain number of Brca1/2 mutants in each cohort, while Propel did not, and indeed the HRR status of Propel patients was only tested subsequently.

As a result the rate of Brca1/2 mutation in Magnitude was perhaps 10 times higher than in Propel, according to Dr Higado. And Zejula’s benefit was especially pronounced in Brca1/2 patients, in whom risk of radiographic progression was cut by 50% versus Zytiga alone.

This brings up a separate point about Zejula, namely should it be used in all HRR-positives? Dr Higado said no, at least not until overall survival data matured and more analysis was done on Brca versus non-Brca patients. However, she did suggest that Zejula might be used in Brca1/2 disease now, before OS data are available.

At Esmo in 2019 Zejula had yielded a promising result in the Galahad trial in third-line prostate cancer patients with the Brca1/2 mutation, but J&J subsequently gave up on this, citing rival approvals that eliminated the accelerated approval possibility. J&J had carved out Zejula’s prostate cancer use from Tesaro in 2016, before Glaxo bought this company out.

Clovis and Pfizer

While Parp inhibitors’ first successes came in ovarian and breast cancers prostate cancer is becoming an increasingly important setting, and one in which Lynparza currently holds the upper hand.

Lynparza secured approval in second-line patients with any type of HRR mutation – a highly controversial decision given that the drug appeared to have virtually no effect against HRR mutations that were not Brca1/2. This hit a third Parp, Clovis’s Rubraca, which secured accelerated approval in third-line disease, but only in Brca1/2 mutants.

The Caspar trial tests Rubraca plus Xtandi in front-line prostate cancer, also seeking to cut the data by HRR status, but its entry cites a primary completion date of May 2023. A fourth Parp, Pfizer’s Talzenna, is in the first-line Xtandi-combo study Talapro-2, which could read out this year.

If either or both of these latecomers do score they might find Lynparza and Zejula already on the market before them. Though not, apparently, without a biomarker controversy that is becoming all too familiar in the Parp space.

Other Parp inhibitor prostate cancer studies to watch
Drug Company Trial Setting Study type Primary completion
Talzenna Pfizer Talapro-2 1L, Xtandi combo Registrational Mar 2022
Rubraca Clovis Caspar 1L, Xtandi combo Registrational May 2023
Triton3 2L, vs Zytiga or Xtandi Confirmatory Feb 2022

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