In this edition of “How I will treat my next patient,” I review two recent presentations at the European Society of Medical Oncology Congress regarding the expanded use of poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi) in patients with advanced solid tumors, potentially broadening the indications for this important class of agents.
Perhaps 25% of prostate cancer patients have loss-of-function mutations – BRCA1, BRCA2, and ATM – or alterations in homologous recombinant repair (HRR) genes. In the PROfound trial, men with metastatic castration-resistant prostate cancer (mCRPC) who had progressed on either abiraterone or enzalutamide and who had DNA-repair mutations were randomized to either olaparib (300 mg b.i.d.) or treatment of physician’s choice (TPC) with either abiraterone or enzalutamide plus prednisone (Hussain M et al. ESMO 2019, Abstract LBA-12).
Two cohorts were enrolled. Cohort A included 245 men with BRCA1, BRCA2, or ATM mutations, and cohort B included 142 men with other alterations (BARD1, BIRP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD15B, RAD15C, RAD15D, or RAD54L). After disease progression, patients could cross over to receive PARPi, which more than 80% of patients eventually did.
Median radiographic progression-free survival (PFS) in cohort A was 7.39 months with PARPi, compared with 3.55 months with TPC, for a hazard ratio for progression on PARPi of 0.34 (P less than .0001). A significant benefit was seen for PARPi in the overall population (both cohorts), with a median radiographic PFS of 5.82 months va. 3.52 months, respectively (HR, 0.49; P less than .0001).
Among patients in cohort A, the objective response rate (ORR) was 33.3% with PARPi, compared with 2.3% for TPC, resulting in an odds ratio for ORR of 20.86 (P less than .0001).
PARPi demonstrated a longer time to pain progression in cohort A, with the median not reached, compared with 9.92 months with TPC (HR, 0.44; P = .0192). Perhaps because of the high proportion of TPC patients who eventually received PARPi, no statistically significant differences in overall survival have yet been seen.
What this means in practice
During my fellowship, a mentor taught that “because quality of life is generally better before progression than afterwards, PFS is a worthy endpoint in its own right.” For that reason, although I would have liked to see the data for cohort B alone, it appears worthwhile for physicians to make every effort to obtain PARPi. The difference in ORR, pain progression, and PFS at 12 months is clinically dramatic.
Of equal significance, however, is that PROfound is the first positive phase 3 biomarker-selected study evaluating a targeted treatment in patients with mCRPC. For prostate cancer – as for breast, ovarian, pancreatic, and several other cancers – the molecular biology and genetic background of our patients dictates the other tumors for which they and their family members are at risk, and expands the treatment armamentarium for them.
For those clinicians who needed to be convinced that “precision medicine” for prostate cancer patients was worthwhile, the PROfound trial should have a profound impact.