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Olaparib for Metastatic Castration-Resistant Prostate Cancer
Johann de Bono1, Joaquin Mateo1, Karim Fizazi1
1From the Institute of Cancer Research and Royal Marsden Hospital, London (J. de Bono), and AstraZeneca, Translational Medicine, Cambridge (C.A.A.) - all in the United Kingdom; Vall d'Hebron Institute of Oncology and Vall d'Hebron University Hospital, Barcelona (J.M.), the Spanish National Cancer Research Center, Madrid (D.O.), and Hospitales Universitarios Virgen de la Victoria y Regional de Málaga, Malaga (D.O.) - all in Spain; Institut Gustave Roussy, University of Paris Sud, Villejuif (K.F.), and the Department of Medical Oncology, Centre Hospitalier Universitaire Besançon, Besançon (A.T.-V.) - all in France; Centre Hospitalier de l'Université de Montréal-Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal (F.S.), and BC Cancer Agency, Vancouver (K.N.C.) - all in Canada; Carolina Urologic Research Center, Myrtle Beach, SC (N.S.); Peter MacCallum Cancer Centre, Melbourne, VIC, Australia (S.S.); Tulane University School of Medicine, New Orleans (O.S.); Huntsman Cancer Institute, University of Utah Comprehensive Cancer Center, Salt Lake City (N.A.); John Wayne Cancer Institute, Santa Monica, CA (P.T.); Radboud University Medical Center, Nijmegen, the Netherlands (N.M.); AstraZeneca, Global Medicines Development, Oncology, Gaithersburg, MD (C.G., J.K., W.W.); Merck, Kenilworth, NJ (J. Burgents); AstraZeneca, Precision Medicine, Oncology Research and Development, Gaithersburg, MD (A.K.); and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago (M.H.).
Background:
Multiple loss-of-function alterations in genes that are involved in DNA repair, including homologous recombination repair, are associated with response to poly(adenosine diphosphate-ribose) polymerase (PARP) inhibition in patients with prostate and other cancers.
Methods:
We conducted a randomized, open-label, phase 3 trial evaluating the PARP inhibitor olaparib in men with metastatic castration-resistant prostate cancer who had disease progression while receiving a new hormonal agent (e.g., enzalutamide or abiraterone). All the men had a qualifying alteration in prespecified genes with a direct or indirect role in homologous recombination repair. Cohort A (245 patients) had at least one alteration in BRCA1, BRCA2, or ATM; cohort B (142 patients) had alterations in any of 12 other prespecified genes, prospectively and centrally determined from tumor tissue. Patients were randomly assigned (in a 2:1 ratio) to receive olaparib or the physician's choice of enzalutamide or abiraterone (control). The primary end point was imaging-based progression-free survival in cohort A according to blinded independent central review.
Results:
In cohort A, imaging-based progression-free survival was significantly longer in the olaparib group than in the control group (median, 7.4 months vs. 3.6 months; hazard ratio for progression or death, 0.34; 95% confidence interval, 0.25 to 0.47; P<0.001); a significant benefit was also observed with respect to the confirmed objective response rate and the time to pain progression. The median overall survival in cohort A was 18.5 months in the olaparib group and 15.1 months in the control group; 81% of the patients in the control group who had progression crossed over to receive olaparib. A significant benefit for olaparib was also seen for imaging-based progression-free survival in the overall population (cohorts A and B). Anemia and nausea were the main toxic effects in patients who received olaparib.
Conclusions:
In men with metastatic castration-resistant prostate cancer who had disease progression while receiving enzalutamide or abiraterone and who had alterations in genes with a role in homologous recombination repair, olaparib was associated with longer progression-free survival and better measures of response and patient-reported end points than either enzalutamide or abiraterone. (Funded by AstraZeneca and Merck Sharp & Dohme; PROfound ClinicalTrials.gov number, NCT02987543.).
Insights
Olaparib significantly improved progression-free survival in men with metastatic castration-resistant prostate cancer and DNA repair gene alterations. This PARP inhibitor offers a new treatment option for advanced prostate cancer patients.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Loss-of-function alterations in DNA repair genes, including homologous recombination repair (HRR), are linked to cancer treatment response.
- Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors have shown promise in various cancers with specific genetic profiles.
Purpose of the Study:
- To evaluate the efficacy of the PARP inhibitor olaparib compared to standard hormonal agents in men with metastatic castration-resistant prostate cancer (mCRPC).
- To assess olaparib's effectiveness in patients with documented alterations in HRR-related genes.
Main Methods:
- A randomized, open-label, phase 3 trial (PROfound) involving men with mCRPC who progressed on enzalutamide or abiraterone.
- Patients were selected based on qualifying alterations in prespecified HRR genes (BRCA1, BRCA2, ATM, or others).
- Participants were randomized 2:1 to receive olaparib or physician's choice of enzalutamide/abiraterone, with imaging-based progression-free survival as the primary endpoint.
Main Results:
- In cohort A (BRCA1/2, ATM alterations), olaparib significantly extended median progression-free survival (7.4 vs. 3.6 months) and improved objective response rates.
- Overall survival showed a trend favoring olaparib, with high crossover rates from the control arm.
- Significant benefits for olaparib were observed in the overall study population (cohorts A and B) for progression-free survival.
Conclusions:
- Olaparib demonstrated superior efficacy over enzalutamide or abiraterone in men with mCRPC and HRR gene alterations.
- The study supports olaparib as a targeted therapy option for prostate cancer patients with specific DNA repair defects.
- Key toxicities associated with olaparib included anemia and nausea.
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