Results from the PROfound phase III study, funded by AstraZeneca and Merck Sharp & Dohme, open up a much-needed new treatment avenue for the more precise and effective treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) whose disease has progressed with hormonal therapy.

The PROfound trial investigators show significantly longer overall survival of mCRPC patients with at least one alteration in BRCA1, BRCA2, or ATM genes, who received treatment with PARP inhibitor olaparib versus enzalutamide or abiraterone plus prednisone.

Ringing in a new era of precision medicine to more effectively combat this lethal disease, it is the first time that a PARPi has shown an increased survival rate in a prospective clinical trial.

PROfound also demonstrates the importance of incorporating genomic sequencing for the optimal stratification of mCRPC patients.

In the quest to establish more potent treatment strategies that target vulnerabilities in BRCA1/2-associated cancers , PARP inhibitor (PARPi) olaparib continues to drive more precise and personalised therapeutic approaches.

By extending survival and reducing risk of disease progression, this anti-cancer therapy has been approved for the treatment of both BRCA1/2 mutated advanced breast and ovarian cancers, and is also licensed as maintenance therapy after response to platinum-based chemotherapy for the latter.

Revealed today during the second Presidential Session of the European Society for Medical Oncology's (ESMO) Virtual Congress 2020 (19-21 September), findings from the PROfound open-label, randomised phase III study evidence the efficacy of olaparib for the targeted treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) with at least one alteration in BRCA1, BRCA2, or ATM genes.

Presented by second author Joaquin Mateo, Principal Investigator of the Vall d'Hebron Institute of Oncology's (VHIO) Prostate Cancer Translational Research Group, this practice-changing data has published simultaneously as an Original Article in the New England Journal of Medicine.

Building on previous findings first-authored by Joaquin Mateo, showing that olaparib leads to tumour responses in mCRPC patients with DNA-damage repair (DDR) alterations who had previously received chemotherapy and were no longer responding to standard treatments, the PROfound investigators now show significantly longer overall survival in this patient population who were treated with olaparib versus standard therapy with enzlutamide or abiraterone plus prednisone.

This present research, spearhead by Maha Hussain, the Robert H. Lurie Comprehensive Cancer Center (Chicago, USA), and Johann de Bono, the Institute of Cancer Research and Royal Marsden (London, UK), has led to the approval of olapirib by the U.S. Food and Drug Administration (FDA) for the treatment of this disease.

In addition, clinical guidelines have been elaborated by ESMO, the National Comprehensive Cancer Network (NCCN), and American Urological Association (AUA), among others, that now recommend genomic sequencing of patients with advanced prostate cancer to identify which patients would most likely benefit from this novel and personalised treatment approach.

Commenting for VHIO's Global Communications second author of the study, Joaquin Mateo, who is also a Medical Oncologist at the Vall d'Hebron University Hospital (Vall d'Hebron Barcelona Hospital Campus) said, "The relevance of our results is reflected by the fact that the FDA has already authorised olaparib for the treatment of metastatic castration-resistant prostate cancer. Based on these data, this week the European Medicines Agency recommended the approval of olaparib for prostate cancer patients with BRCA1 or BRCA2 mutations, irrespective of somatic or germline. We expect to have the treatment available for patients in the clinic soon."

The PROfound Trial consisted of two cohorts: A included 245 patients with at least one alteration in BRCA1, BRCA2 or ATM, the most common and well-known mutations in this subtype of prostate tumours, and B with 142 patients who had a least one alteration in any of the other 12 prespecified genes.

Alterations in these genes, whose function is related to BRCA1 or BRCA2, are found in between 10-15% of these cancers.

"Cohort B was more exploratory given that there is little data on these genes individually. We sought to establish whether any of the twelve might be as relevant as those in cohort A in identifying patients who may benefit from olaparib. More information on these less frequent subgroups is required because some may well be important," noted Joaquin.

The ratio of patients treated with olaparib to patients treated with standard drugs was 2 to 1, with 256 patients treated with olaparib and 131 with hormonal therapy (enzalutamide or abiraterone plus prednisone). All patients had previously received hormonal therapy.

The results showed that the median survival increased, particularly in cohort A, in which the survival rate increased from 14.7 months with standard treatment to 19.1 months in the olaparib arm of the study, which indicates a reduced risk of death of 31%.

In cohort B, the survival rate increased from 11.5 months to 14.1 months.

"While our results show that olaparib is effective in patients with DNA repair gene mutations, even within this group we identified differences depending on the specific gene of each patient. Mutations in BRCA1 and BRCA2 are those clearly associated with the greatest benefit. For genes whose mutations are not very prevalent, more studies are warranted," added Joaquin.

By showing that certain genomic profiles benefit from treatment with olaparib, this study represents a paradigm shift in the treatment of this subpopulation of patients.

Specifically, it supports the implementation of genomic stratification of patients with mCRPC, who do not respond to treatment with hormonal therapy in clinical practice based on tumour sequencing.

He concluded, "This gene-targeted approach could help more precisely guide treatment decisions as well as match more effective therapies to the molecular make up of individual patients' tumours. The challenge that lies ahead will be implementing genomic testing in clinical practice, especially because, unlike breast or ovarian cancer, these BRCA1 or BRCA2 mutations are not necessarily hereditary. It is therefore imperative to sequence tumour biopsies, beyond just normal tissues or blood from patients."

Source: VHIO

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