Data from the PROfound trial reported at ESMO

From a report presented by Hussain yesterday at the annual meeting of the European Society for Medical Oncology (ESMO) we gained detailed insight into the results of the PROfound trial of olaparib (Lynparza), which had been said to be positive last August. A new and detailed media release can be found here.

The trial was carried out in 387 men with metastatic castration-resistant prostate cancer (mCRPC) who all had mutations in homologous recombination repair (HRRm) genes and whose disease had progressed on prior treatment with new hormonal agent (e.g. abiraterone or enzalutamide). Trial data analysis was then carried out for men in two cohorts: the primary endpoint was in those with mutations in BRCA1/2 or ATM genes; then, if olaparib had clinical benefit, a further, formal analysis was performed of the overall trial population of men with HRRm genes (i.e., BRCA1/2, ATM, CDK12, and 11 other HRRm genes to provide a key secondary endpoint).

So the 387 patients were randomized to treatment with olaparib or to staying on one of the newer androgen deprivation agents (e.g., abiraterone acetate or enzalutamide)

Here are the results for the primary endpoint:

  • Patients treated with olaparib had an average (median) radiographic progression-free survival (rPFS) of 7.4 months.
  • Patients treated with one of the “new” forms of androgen deprivation therapy had an average rPFS of 3.6 months.
  • Treatment discontinuation rates as a consequence of adverse events were
    • 16.4 percent for the patients on olaparib
    • 8.5 percent for the patients on the new forms of ADT

Thus treatment with olaparib reduced the risk of disease progression or death by 66 percent  — equivalent to a hazard ratio [HR] of 0.34 for these men.

The trial also met the key secondary endpoint of rPFS in the overall HRRm population, in which olaparib reduced the risk of disease progression or death by 51 percent (HR = 0.49) and improved rPFS to a median of 5.8 months vs. 3.5 months for abiraterone or enzalutamide.

With respect to effects on overall survival, the interim data have shown a trend toward improvement in overall survival (OS) in each of the two subgroups of patients:

  • Patients with BRCA1/2- or ATM-mutated tumors had
    • An average (median) OS of 18.5 months if treated with olaparib
    • A median OS of 15.1 months if treated with abiraterone or enzalutamide
  • Patients in the overall HRRm cohort had
    • An average (median) OS of 17.5 months if treated with olaparib
    • A median OS of 14.3 months if treated with abiraterone or enzalutamide

These data make it highly likely that the US Food and Drug Administration will soon approve olaparib as a treatment for all men with mCRPC who carry HRRm genes (inclusive of mutations in BRCA1/2 or ATM genes).

An important question that still needs to be answered is whether these drugs can offer greater benefit to such subsets of men with advanced prostate cancer if they can be given earlier in the course of the patients’ disease.

A second key question will be whether one of the other PARP inhibitors currently in clinical trials can demonstrate greater efficacy or fewer side effects or both.

3 Responses

  1. I will be interested to see if the FDA approves based on this interim analysis, especially since overall survival did not yet reach their benchmark because the number of deaths was too low after about a year of median follow-up. However, since Lynparza is already approved for ovarian and breast cancer, you may be right that they will accept the lower bar (rPFS) for the new indication. Their analysis of the crossovers of Xtandi/Zytiga progressors may help too.

    It is also worth noting that there were similarly good responses in a Phase II trial of another PARP inhibitor (niraparib) for biallelic BRCA1/2 mutations vs other DNA repair mutations (see

    And that men with CDK12 mutations (one of the DNA repair mutations in Cohort B of the PROfound trial) unsurprisingly did not respond to PARP inhibitors (see here.

  2. Interestingly, the FDA granted “breakthrough designation” today for niraparib based on that Phase II trial.

  3. In practice, we are aware of several men who have been approved by their insurance carriers for off-label use of olaparib with a BRCA, ATM or CDK12 mutation going back to 2015.

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