Tolerability of abiraterone (abi) combined with olaparib (ola) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Further results from the phase III PROpel trial.

Abstract

5019 Background: The Phase III PROpel (NCT03732820) trial demonstrated at interim analysis a statistically significant clinical benefit from combining ola + abi in the first-line (1L) mCRPC setting vs placebo (pbo) + abi. Benefit was seen irrespective of a pt’s homologous recombination repair mutation (HRRm) status; median radiographic progression-free survival (rPFS) 24.8 for ola + abi vs 16.6 months for pbo + abi (hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.54–0.81; P<0.0001). The safety profile of ola + abi was shown to be consistent with that for the individual drugs. We report additional interim safety analysis from PROpel. Methods: Eligible pts were ≥18 years with mCRPC, had received no prior chemotherapy or next-generation hormonal agent treatment at mCRPC stage, and were unselected by HRRm status. Pts were randomized 1:1 to abi (1000 mg qd) plus prednisone/prednisolone with either ola (300 mg bid) or pbo. Primary endpoint was investigator-assessed rPFS. Safety was assessed in all pts receiving ≥1 dose of study treatment by adverse event (AE) reporting (CTCAE v4.03). Results: 398 pts received ola + abi and 396 pbo + abi (safety analysis set). At data cut-off (July 30, 2021), median total duration of exposure for ola was 17.5 vs 15.7 months for pbo, and for abi 18.2 months in the ola + abi arm and 15.7 in the pbo + abi arm. Anemia (n=183) was the most common AE in the ola + abi arm, and 34% of these 183 events were managed by dose interruption, 23% by dose reduction, and 8% resulted in treatment discontinuation. Anemia and pulmonary embolism (PE) were the only Grade ≥3 AEs in ≥5% of pts (anemia: ola + abi, 15.1% vs pbo + abi, 3.3%; PE: 6.5% vs 1.8%, respectively). Most PEs were detected incidentally on radiographic imaging (69.2% and 71.4% in the ola + abi and pbo + abi arms, respectively) and no pts discontinued. More pts in the ola + abi arm experienced venous thromboembolism (Table). Arterial thromboembolism and cardiac failure AEs were balanced between the treatment arms. No AE of myelodysplastic syndrome/acute myeloid leukemia was reported in either treatment arm. COVID-19 was reported more frequently with ola + abi (8.3% vs 4.5%). Conclusions: PROpel demonstrated a predictable safety profile for ola + abi given in combination to pts with 1L mCRPC unselected by HRRm status. AEs of cardiac failure and arterial thromboembolism were reported at similar frequency in both treatment arms. The majority of PEs were asymptomatic. The safety profile of abiraterone was not adversely impacted by its combination with olaparib. Clinical trial information: NCT03732820. [Table: see text]

Cardioprotective Effects of PARP Inhibitors: A Re-Analysis of a Meta-Analysis and a Real-Word Data Analysis Using the FAERS Database

“…Ultimately, only seven studies from the previous meta-analysis were selected. The characteristics of the selected studies are summarized in Table 1 [ 14 , 15 , 16 , 17 , 18 , 19 , 20 ].…”

“…Ultimately, only seven studies from the previous meta-analysis were selected. The characteristics of the selected studies are summarized in Table 1 [14][15][16][17][18][19][20]. Figure 2 presents a forest plot illustrating the impact of co-administration of PARP inhibitors.…”

Parp Inhibitors and Radiotherapy: A New Combination for Prostate Cancer (Systematic Review)

“…Recently, some phase III clinical trials have shown the benefit of the combination of a PARPi with a new antiandrogen in the first-line setting of mCRPC. The PROpel trial [ 67 ] demonstrated an improvement in rPFS (HR 0.66 [95% CI 0.54–0.81]) of the combination of olaparib and abiraterone compared to abiraterone alone, irrespective of the HRR mutation status. On the other hand, preliminary results from MAGNITUDE showed the benefit of the combination of Niraparib and Abiraterone, with an improvement in the rPFS (relative risk 0.53, 95% CI: 0.36–0.79, p = 0.0014) and a reduction in the risk of disease progression/death (47% vs. 27%) in mCRPC with alterations in genes associated with HRR [ 68 ].…”

“…This clinical trial [ 103 ] opens the door for a new horizon in PCa treatment. Actually, there is enough preclinical evidence that encourages the use of PARPi and RT [ 92 , 93 , 94 , 95 , 96 , 97 , 98 ]; abundant clinical evidence that supports the positive effect of combining PARPi and ADT [ 63 , 64 , 65 , 66 ] as well as PARPi and new antiandrogens [ 67 , 68 ]; and solid evidence for the use of RT and ADT [ 99 , 100 ]. So maybe it is time to explore the combination of the three therapies.…”

Use of PARP inhibitors in prostate cancer: from specific to broader application

“…These patients were not selected on the basis of biomarker criteria, suggested that they might benefit from the combination treatment irrespective of HRR mutation status (46). The PROpel study (47) presented at the 2022 annual meeting of the American Society of Clinical Oncology (ASCO) further demonstrated that olaparib plus AA, as the first-line therapy for mCRPC (including patients with HRR mutated and HRR-non-mutated), significantly prolonged rPFS in patients compared with the placebo plus AA group (24.8 vs. 16.6 months, P<0.0001). Preliminary results from the MAGNITUDE study (48) reported that niraparib plus AA significantly improved rPFS (relative risk 0.53, 95% CI: 0.36-0.79, P=0.0014) and reduced the risk of disease progression/death (47% vs. 27%) in the BRCA1/2 mutation subgroup of mCRPC.…”