Olaparib for Metastatic Castration-Resistant Prostate Cancer

[Balsam01]

TAKE-HOME MESSAGE

•In this phase III study, 387 patients with metastatic castration-resistant prostate cancer (mCRPC) and DNA repair gene defects who progressed on abiraterone or enzalutamide were randomized in a 2:1 ratio to olaparib (PARP inhibitor) or physician's choice of enzalutamide or abiraterone. Patients in cohort A had at least one alteration in BRCA1, BRCA2, or ATM; those in cohort B had alterations in any of 12 other prespecified genes. The primary endpoint was imaging-based progression-free survival (PFS) in cohort A. In cohort A, olaparib was associated with significantly longer imaging-based PFS (HR, 0.34; P < .01), higher objective response rate, and longer time to pain progression compared with the control group.

•This is a very important and practice-changing study because it's the first phase III trial showing superiority of a PARP inhibitor for patients with mCRPC and DNA repair gene alterations, validating the importance of biomarker testing for men with metastatic disease. In addition, this study met the overall survival endpoint for olaparib (data now shown; press release, April 2020).

– Pedro C. Barata, MD

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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.

The New England Journal of Medicine

Olaparib for Metastatic Castration-Resistant Prostate Cancer

N. Engl. J. Med 2020 Apr 28;[EPub Ahead of Print], J de Bono, J Mateo, K Fizazi, e

[Balsam01]

If one is BRCA2, should one try the traditional approaches such as Zytiga and say Lupron and, down the line, Chemo and try and hold Olaparib in reserve?

[Balsam01]

No, became detectable two months ago. On ADT vacation still. PSA at .4. Video conf with Johns Hopkins tomorrow. JH doctor stated emphatically that I should not go back on ADT at this point so tomorrow I will learn his theory.

[HopingForTheBest1]

I am BRCA2+. My Oncologist was able to get me approved for "off label" use of Olaparib outside of any clinical trials, after having failed 6 months of Zytiga/Prednisone. Have been on it for 15 months so far, and PSA is undetectable. Also have been on Lupron/Eligard ADT and Xgeva for bone.

[elainea53]

My husband had the phase 2 at mda. He does not have Barca gene. Dr stopped it as was not working

[Maleko808]

Totally agree with you. My MO has me on a trial the includes Xtandi and talazoparib ( or placebo) but becuase of our FDA the results and benefit to others eont be known for years. My MO is convinced that paribs are an effective option and that they should be available now.