PARP Inhibitors Do Not Restore Zytiga Sensitivity in Prostate Cancer
PARP inhibitors do not restore sensitivity to Zytiga (abiraterone) after resistance has developed; instead, they represent an alternative treatment strategy for patients who have progressed on abiraterone, particularly those with homologous recombination repair (HRR) gene mutations. 1
Evidence Against Restoration of Abiraterone Sensitivity
The clinical trial data clearly demonstrate that PARP inhibitors are used after progression on abiraterone, not to restore sensitivity to it:
The PROfound trial specifically enrolled patients with mCRPC who had progressed on abiraterone or enzalutamide, comparing olaparib to physician's choice of abiraterone/enzalutamide (agents on which patients had already failed). 1
Olaparib showed superior radiographic PFS compared to continuing abiraterone/enzalutamide in patients with BRCA1/2 or ATM mutations (HR 0.34; 95% CI, 0.25-0.47; P<0.001), indicating it works as an alternative mechanism, not by restoring prior sensitivity. 1
The FDA approval for olaparib explicitly requires prior treatment with enzalutamide or abiraterone, positioning it as a subsequent-line therapy rather than a re-sensitization strategy. 1
The Combination Strategy: A Different Approach
There is evidence for combining PARP inhibitors with abiraterone upfront, but this is mechanistically distinct from restoring sensitivity:
The PROpel trial demonstrated that combining olaparib with abiraterone from the start (before resistance develops) improved imaging-based PFS compared to abiraterone alone (24.8 vs 16.6 months; HR 0.66; 95% CI, 0.54-0.81; P<0.001) in treatment-naïve mCRPC patients. 1
This combination works through complementary mechanisms: preclinical data show that androgen receptor inhibitors downregulate DNA repair genes, creating synthetic lethality when combined with PARP inhibition, rather than reversing acquired resistance. 1
The combination benefit occurred regardless of HRR mutation status, suggesting a different mechanism than simply exploiting pre-existing DNA repair defects. 1
Clinical Algorithm for PARP Inhibitor Use
For patients who have progressed on abiraterone:
Test for HRR gene mutations (BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, RAD54L) using somatic tumor, ctDNA, or germline testing. 1, 2
If BRCA1/2 mutations are present: Use olaparib (300 mg twice daily) or rucaparib as alternative therapy (Category 1 recommendation). 1
If ATM mutations are present: Olaparib is an option, though response rates are lower than with BRCA1/2 mutations. 1
If other HRR mutations (CHEK2, CDK12, etc.) are present: Olaparib may be considered, but counsel patients that response rates are substantially lower than BRCA1/2 mutations, as these genes were in Cohort B of PROfound which failed to meet its primary endpoint. 1, 3
For treatment-naïve mCRPC patients:
Consider upfront combination of olaparib plus abiraterone based on PROpel trial data, regardless of HRR mutation status. 1
This is a prevention strategy, not restoration of sensitivity, as it prevents resistance development through complementary mechanisms. 1
Critical Pitfalls to Avoid
Do not attempt to "re-challenge" with abiraterone plus a PARP inhibitor after abiraterone failure – there is no clinical trial evidence supporting this approach. 1
Do not overestimate PARP inhibitor efficacy in non-BRCA mutations: The PROfound trial showed minimal activity in ATM, CDK12, and other HRR gene mutations, with Cohort B failing its primary endpoint. 1, 3
Monitor closely for anemia (20% grade 3/4), fatigue, nausea, and thrombocytopenia with complete blood counts every 2-4 weeks initially, then monthly, with transfusion support and dose reductions as needed. 4, 3
Recognize that PPP2R2A mutations showed unfavorable risk/benefit profiles in PROfound and olaparib should not be used in these patients. 1
The Bottom Line
PARP inhibitors function as an alternative treatment pathway exploiting DNA repair deficiencies, not as agents that restore sensitivity to prior hormonal therapies. The only validated approach combining these drug classes is upfront combination therapy before resistance develops, which works through complementary mechanisms rather than reversing acquired resistance. 1