PROpel: Olaparib and Abiraterone for Patients with mCRPC
A comprehensive overview of the study design and findings from the PROpel trial, which looked at olaparib and abiraterone in patients with metastatic castration-resistant prostate cancer.
Case: A 65-Year-Old Man With Prostate Cancer
January 2018
Initial Presentation
- A 65-year-old man was diagnosed with localized prostate cancer
- Biopsy revealed adenocarcinoma of the prostate gland, Gleason score 7 [4+3]
- PSA 15.7 ng/mL
- Baseline staging: T3bN1M0 with right seminal vesicle and pelvic lymph node involvement
Initial Treatment
- He undergoes radical prostatectomy with PLND
- PSA nadir of 0.4 ng/mL post-surgery
- Gleason 7 (4 + 3) confirmed
- Positive surgical margins
- Baseline staging confirmed – AJCC Stage IVA
February 2019
Follow-Up Notes
- Serum PSA, 38 ng/mL; ALP, 289 IU/L
- PSMA PET CT:
- Metastatic retroperitoneal LNs outside resection field
- Abdominal nodes
- Bone mets in ribs and thoracic spine
- Genetic testing: BRCA2 mutation-positive
Additional Treatment
- Abiraterone + prednisone initiated
- Improved pain, PSA, and ALP
October 2019
Follow-Up Notes
- Patient reported bone pain
- Laboratory testing revealed rising PSA and ALP (serum PSA, 350 ng/mL; ALP, 2500 IU/L)
- Imaging showed radiologic progression
- ECOG PS 1
- PSMA PET CT: increased uptake in retroperitoneal and abdominal LNs
mCRPC Treatment
- Treated with docetaxel x4 cycles and denosumab
- Serum PSA, 38 ng/mL; ALP, 289 IU/L
- Reporting bone pain increased in back, now reporting pain in hip area
- Bone scan and CT scan:
- Enlargement of retroperitoneal and abdominal LNs
- Additional bone mets noted in pelvic region
Transcript:
Daniel J. George, MD: The last year or so has brought a change to our paradigm in treating metastatic castrate-resistant prostate cancer, and it came from the PROpel study [NCT03732820] that was initially published in 2022, and with a subsequent survival update in 2023. This was a novel design. Previously, we had seen that PARP inhibitors, which blocked the DNA repair mechanisms associated with homologous recombinant repair, PARP inhibitors were shown to be beneficial in patients with homologous recombinant repair defects, including BRCA defects, and were FDA-approved in [the] metastatic castrate-resistant disease setting following a novel hormonal agent based on the PROfound [NCT02987543] data. But what was also found in an earlier study was that in patients who were starting on a novel hormonal agent in the metastatic castrate-resistant setting, adding a PARP inhibitor could add to the clinical benefits. This was studied in a randomized phase 2 study that demonstrated a progression-free survival benefit.
The PROpel study was a phase 3, global, definitive study to compare patients with metastatic castrate-resistant prostate cancer starting on a novel hormonal agent. In this case, abiraterone [Zytiga] to be randomized to either placebo or olaparib [Lynparza], the PARP inhibitor, and in an all-comer population that included patients with homologous recombinant repair defects and BRCA defects. Patients were randomized 1 to 1 to either abiraterone or abiraterone plus olaparib, and followed for radiographic progression by blinded independent review, as well as for secondary end points including overall survival. This was an 800 patient trial, and showed in its intention-to-treat population was a 40% improvement in the time to radiographic progression, so an rPFS [radiographic progression-free survival] benefit with a hazard ratio of 0.60. So really significant improvement.
The control arm of abiraterone alone of 16.6 months was identical to the median rPFS that we saw in the COU-AA-302 trial [NCT00887198], the pivotal trial for that agent. This was emblematic of the patient population treated in prior metastatic castrate-resistant prostate cancer populations, but we saw a 24-month median rPFS associated with the combination of abiraterone and olaparib, which was an 8-month improvement in the radiographic progression-free survival. This was seen across the population, and it was actually broken down in subsets of those with BRCA mutation, which was about 10% of the population, versus the 90% population that had non-BRCA mutations. There was benefit in both groups, and the BRCA group was dramatic. The combination effect in addition to having a BRCA mutation led to a dramatic radiographic progression-free survival. The median was not reached, but the overall hazard ratio was 0.28.
In the non-BRCA mutated population, so all comers excluding the BRCA population, there was also a radiographic progression-free survival benefit with a hazard ratio of 0.76, 95% confidence interval, that didn’t cross the 1 threshold. So, significant, and with a median improvement in radiographic progression-free survival of 5 months. That was by investigator assessment. This is the real-world practice assessment of outcomes demonstrating that benefit.
Finally, the overall survival for the overall intention-to-treat population was powered. It was a secondary end point, but it showed a trend improving the overall survival with a hazard ratio in the final analysis of 0.81. It didn’t quite meet the significance threshold, the P value of 0.053, and I think the threshold was 0.037. So it wasn’t quite significant, but there was a strong trend for overall survival in association with that population. What was significant, and even though the numbers were small, was that 10% of BRCA-mutated populations, where again, the benefit here was dramatic with an overall survival that was not reached in the BRCApopulation. With olaparib, and compared to the abiraterone-alone arm, the hazard ratio was 0.29. So a very significant benefit to that population. It was this population of patients with known BRCA mutations in combination with olaparib that led to the FDA approving this regimen of abiraterone and olaparib for those patients with BRCA-mutated tumors because these results were so compelling.
I will add that safety is always a concern, and the safety associated with PARP inhibitors is well-known and well-established. We can see anemia associated with these agents, and in this setting with abiraterone, that was no different. We did see about a 40% incidence of anemia and roughly 18% or so requiring transfusion; that is a necessary support for some patients. Dose reductions were also seen, and some patients had to discontinue therapy because of persistent anemia or other causes.
Overall, 80-plus percent of the patients were able to tolerate the drug and benefit from it. Anemia is a measurable and treatable toxicity, and in almost all the cases of anemia, the high-grade anemias were seen in the first 3 months, so patients were managed with dose interruptions or reductions or discontinuations. Then after that, most patients were able to continue without recurrent episodes. Other side effects include GI [gastrointestinal] side effects. Some nausea and diarrhea that were generally low grade. So overall, a well-tolerated regimen. There was a small incidence of pulmonary embolism, about 5%, that was seen, and again, most of these were incidental findings on CT scan and managed with anticoagulation. Overall, the toxicity profile didn’t affect the efficacy results, the quality of life results, and the benefits that we saw particularly in the BRCA-mutated population.
Transcript edited for clarity.
