And now … FDA approves second PARP inhibitor for selected men with mCRPC


Following last week’s approval of rucaparib (Rubraca), the US Food and Drug Administration (FDA) has now, also, approved the PARP inhibitor olaparib (Lynparza) for the treatment of men with with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC) who have progressed following prior treatment with enzalutamide or abiraterone.

A detailed media release was issued late yesterday by Merck and AstraZeneca. The media release provides more information about this approval, which was based on data from the Phase III PROfound trial, reported by de Bono et al. in the New England Journal of Medicine in April. A brief report on the results of the PROfound trial was issued on this web site on April 27 this year..

Some key points from this media release are worth noting:

  • HRR gene mutations occur in 20 to 30 percent of patients with mCRPC.
  • Compared to treatment with enzalutamide or abiraterone, in men with mCRPC selected for BRCA1/2 or ATM gene mutations, the primary endpoint and a subpopulation of HRR gene mutations
    • Olaparib lowered risk for disease progression or death by 66 percent (hazard ratio [HR] = 0.34).
    • Olaparib roughly doubled radiographic progression-free survival (rPFS) to an average (median) of 7.4 months vs. 3.6 months.
  • Compared to treatment with enzalutamide or abiraterone in the overall trial population of men with HRR gene-mutated mCRPC,
    • Olaparib reduced the risk of radiographic disease progression or death by 51 percent (HR = 0.49).
    • Olaparib improved rPFS to a median of 5.8 months vs. 3.5 months.
  • Compared to treatment with enzalutamide or abiraterone, in men with mCRPC selected for BRCA1/2 or ATM gene mutations, a secondary endpoint showed that olaparib improved overall survival to a median of 19.1 vs. 14.7 months.

However, it should also be noted that there was a significant risk for adverse events associated with treatment with androgen deprivation therapy (ADT) + olaparib as compared to treatment with ADT + enzalutamide or abiraterone acetate, as follows:

  • Venous thromboembolic events, including pulmonary embolism, were evident in 7 percent of patients with mCRPC treated with olaparib as compared to 3.1 percent of patients receiving enzalutamide or abiraterone.
  • Common adverse reactions (ARs) among patients treated with ADT + olaparib compared to ADT + enzalutamide or abiraterone included
    • Anemia (46 vs. 15 percent)
    • Nausea (41 vs. 19 percent)
    • fatigue, including asthenia (41 vs. 32 percent)
    • Decreased appetite (30 vs. 18 percent)
    • Diarrhea (21 vs. 7 percent)
    • Vomiting (18 vs. 12 percent)
    • Thrombocytopenia (12 vs. 3 percent)
    • Cough (11 vs. 2 percent), and
    • Dyspnea (10 vs. 3 percent).

The “New” Prostate Cancer InfoLink is obviously delighted to see the first two PARP inhibitors approved in the US for the treatment of advanced forms of prostate cancer. However, we also need to be very clear that these products — at least as yet — have very restricted indications in the treatment of prostate cancer and that they come with additional risks compared to other forms of treatment.

One Response

  1. It should be noted that the big difference between the rucaparib and olaparib approvals is that docetaxel (chemotherapy) is also required prior to the use of rucaparib. It will be interesting to see if the insurers enforce that, or whether they are willing to approve either PARP inhibitor in the presence of an HRR mutation.

    It will also be interesting to see whether they insist on the cancer being castrate resistant. Anecdotally, we have seen off-label approval for men who are metastatic but still castrate sensitive.

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