PARP inhibition in selected patients slows progression on advanced prostate cancer

Data from the phase 3 PROfound trial, presented by Prof. Maha Hussain (Northwestern University, Chicago, USA) showed that olaparib delayed cancer progression by about 4 months compared with new hormonal agents (enzalutamide or abiraterone acetate) in patients with metastatic, pre-treated prostate cancer (mCRPC) whose cancer cells had faulty DNA repair genes. Preliminary data showed that treatment also prolonged overall survival by over 3 months [1].

The PROfound trial compared the efficacy of the poly-ADP ribose polymerase (PARP) inhibitor olaparib with the physician’s choice of new hormonal agent treatment with enzalutamide or abiraterone. Cohort A patients had alterations in BRCA1, BRCA2, or ATM genes while those in Cohort B had alterations in any of 12 other genes known to be involved in DNA repair. Targeting DNA repair pathways in cancer cells is already used to treat breast and ovarian cancer in patients with mistakes in two DNA repair genes, BRCA1 and BRCA2. Changes in other genes that are involved in DNA repair, such as ATM, can also make cancer cells more susceptible to PARP inhibitors.

In Cohort A, median progression-free survival was 7.39 months with olaparib compared with 3.55 months for hormonal treatment (HR 0.34; P<0.0001). In the overall population (Cohort A+B), median progression-free survival was 5.82 vs 3.52 months respectively (HR 0.49; P<0.0001).

Although insufficient deaths had occurred for a conclusive result, interim overall survival analysis in Cohort A showed that median overall survival was 18.5 months with olaparib compared with 15.1 with hormonal treatment (HR 0.64; P=0.0173). Median overall survival in the overall population (Cohort A+B) was 17.5 vs 14.3 months (HR 0.67; P=0.0063) with olaparib vs hormonal treatment respectively. Adverse events were more common with olaparib than with hormonal treatment, though median treatment duration was longer with olaparib (7.4 months) than with hormone treatment (3.9 months). In the olaparib group, 16.4% of patients discontinued treatment due to adverse events, compared with 8.5% on hormonal treatment.

Commenting on the PROfound data, Dr Eleni Efstathiou (MD Anderson Cancer Center, Houston, USA) said: “This is a landmark trial, as it is the first phase 3 trial looking specifically at tumours harbouring a targetable molecular alteration. In patients with such tumours, treatment with olaparib resulted in a 66% greater delay in progression than the new hormonal agents which were used in PROfound. This is impressive because it is considerably higher than the 35-40% improvements with which we have been very satisfied in previous prostate cancer studies, in this more advanced disease setting. There is a trend towards improved survival, but we need to wait for the final analysis.”

1. Hussain M et al. ESMO Congress 2019. Abstract LBA12_PR.

Posted on 26 November, 201915 February, 2024