NEJM Evidence 2022 Jun 3
Abiraterone and Olaparib for Metastatic Castration-Resistant Prostate Cancer
Abstract
Purpose
Preclinical studies and results of a phase 2 trial of abiraterone and olaparib suggest a combined antitumor effect when the poly(adenosine diphosphate[ADP]- ribose) polymerase inhibitor olaparib is combined with next-generation hormonal agent abiraterone to treat metastatic castration-resistant prostate cancer (mCRPC).
Methods
We conducted a double-blind, phase 3 trial of abiraterone and olaparib versus abiraterone and placebo in patients with mCRPC in the first-line setting. Patients were enrolled regardless of homologous recombination repair gene mutation (HRRm) status. HRRm status was determined following enrollment by tumor tissue and circulating tumor DNA tests. Patients were randomly assigned (1:1) to receive abiraterone (1000 mg once daily) plus prednisone or prednisolone with either olaparib (300 mg twice daily) or placebo. The primary end point was imaging-based progression-free survival (ibPFS) by investigator assessment. Overall survival was among the secondary end points.
Results
At this planned primary analysis at the first data cutoff, median ibPFS was significantly longer in the abiraterone and olaparib arm than in the abiraterone and placebo arm (24.8 vs. 16.6 months; hazard ratio, 0.66; 95% confidence interval [CI], 0.54 to 0.81; P,0.001) and was consistent with blinded independent central review (hazard ratio, 0.61; 95% CI, 0.49 to 0.74). At this data cutoff, overall survival data were immature (28.6% maturity; hazard ratio, 0.86; 95% CI, 0.66 to 1.12; P50.29). The safety profile of olaparib and abiraterone was consistent with the known safety profiles of the individual drugs. The most common adverse events in the abiraterone and olaparib arm were anemia, fatigue/asthenia, and nausea.
Conclusion
At primary analysis at this first data cutoff, abiraterone combined with olaparib significantly prolonged ibPFS compared with abiraterone and placebo as first-line treatment for patients with mCRPC enrolled irrespective of HRRm status. (Funded by AstraZeneca and Merck Sharp & Dohme, LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; ClinicalTrials.gov number, NCT03732820.)
Related Questions
For HRRm prostate cancer, will you use olaparib alone or in combination with abiraterone?
The combination of a PARP inhibitor with a next-generation hormonal agent, including the combination of olaparib with abiraterone acetate, is not an FDA-approved combination and I do not recommend using it at this time. Both PROpel and MAGNITUDE showed a PFS benefit for the combination versus abirat...
Given several PARP inhibitors approved or with emerging positive data in castrate resistant prostate cancer, how do you decide which one and when to use?
At this point, it's easy. In the prechemo mCRPC state, the answer is olaparib, but it is expected that rucaparib will be an alternative. In the mCRPC state post chemo, could be either olaparib or rucaparib. The others are not yet approved. We are participating in the trial AMPLITUDE, which is lookin...
For a patient treated with abiraterone for first line metastatic prostate cancer, would you still use a combination of abiraterone/olaparib at a subsequent progression?
No, there is no evidence for this, and in the absence of benefit, I would use single agent olaparib in HRD+ patients only, particularly BRCA2 patients. Ongoing trials like the CASPAR trial will address this question. In addition, there are ongoing trials testing PARP/AR combinations in men with mHSP...
Among non-HRRm castrate resistant prostate cancer patients, are there features predictive of response to PROPEL regimen of abiraterone/olaparib?
There is a theory that abiraterone can lead to changes in the tumor that could make it susceptible to PARP inhibitors. I understand that the clinical trial suggests that this may be the case, but I think we need more information as to whether or not this is actually happening.
What could explain the discordant results between PARP/abiraterone combinations in MAGNITUDE and PROpel in non-HRRm prostate cancer?
This is an important question. I would summarize this below: 1. Differences in study design and patient populations MAGNITUDE allowed prior ARSI (5%), prior exposure to abiraterone for up to 4 mo which could have been selected for patients less sensitive to abiraterone where PARPi combination syner...
Will you offer olaparib + abiraterone for all patients with metastatic castrate resistant prostate cancer based on results of PROPEL trial?
PROpel is clearly positive for its primary endpoint of delaying rPFS significantly in ALL first line mCRPC patients above and beyond abiraterone and prednisone alone. The delay of 8-10 months over an active comparator is significant both statistically and clinically, and is similar to the improvemen...
When and how are you incorporating tumor sequencing to plan treatment of metastatic prostate cancer?
Presently, the main categories of actionable DNA based alterations in advanced prostate cancer are 1) alterations in homologous repair enzymes like BRCA2, and 2) microsatellite instability (MSI high status, mismatch repair gene deficiency). These are actionable as they can lead to the use of a thera...