First-line abiraterone plus olaparib sustains trend for OS improvement in mCRPC

Current standard first-line treatment options for metastatic castration-resistant prostate cancer (mCRPC) provide modest survival benefits. At the 2023 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU 2023), Professor Noel Clarke of The Christie at Salford Royal NHS Foundation Trust in Manchester, UK, presented final prespecified overall survival (OS) analysis results of the phase III PROpel study, which showed a sustained trend for OS improvement associated with olaparib in combination with abiraterone vs standard-of-care (SoC) abiraterone alone in men with mCRPC.

Limitations of current mCRPC treatments
“Patients with mCRPC generally have poor outcomes, with modest radiographic progression-free survival [rPFS] and OS associated with current SoC treatments,” said Clarke.

Median OS after first-line treatment is approximately 3 years in clinical trial settings and <2 years in clinical practice. [Lancet Oncol 2015;16:152-160; Euro Urol 2017;71:151-154; Adv Ther 2021;38:4520-4540] In phase III studies, the androgen receptor (AR) inhibitors, abiraterone and enzalutamide, demonstrated absolute improvements in OS of approximately 4 months vs prednisone alone and placebo, respectively. [Lancet Oncol 2015;16:152-160; Euro Urol 2017;71:151-154]

“Up to half of mCRPC patients receive only one line of active therapy in clinical practice, which highlights the need for better treatment options, especially in the first-line setting,” commented Clarke. [Adv Ther 2021;38:4520-4540]

Combining PARP and AR inhibitors: Rationale and proof of concept
Poly (ADP-ribose) polymerase (PARP) and AR are important components of DNA repair in prostate cancer. PARP activity facilitates repair of DNA single- and double-stranded breaks, while AR binds to DNA and facilitates repair through multiple pathways. PARP also enables AR binding to damaged DNA, further facilitating more DNA repair. [Nat Rev Mol Cell Biol 2017;18:610-621; Cancer Discov 2013;3:1245-1253; Science 2017;355:1152-1158] “Combined PARP and AR pathway inhibition may result in DNA damage and improve anti–prostate cancer efficacy,” Clarke noted. [Nat Commun 2017;8:374; Sci Signal 2017;10:eaam7479]

A phase III trial previously demonstrated that monotherapy with a PARP inhibitor, olaparib, significantly prolonged rPFS and OS vs physician’s choice of enzalutamide or abiraterone in patients with mCRPC positive for homologous recombination repair mutations (HRRm) whose disease progressed while receiving a next-generation hormonal agent. [N Engl J Med 2020;382:2091-2102; N Engl J Med 2020;383:2345-2357]

Meanwhile, a phase II, proof-of-concept study demonstrated clinical efficacy of adding olaparib to the current SoC, abiraterone, in patients with mCRPC regardless of HRRm status who had previously received docetaxel. In this study, abiraterone plus olaparib significantly improved rPFS vs abiraterone plus placebo (median, 13.8 months vs 8.2 months; hazard ratio [HR], 0.65; 95 percent confidence interval [CI], 0.44–0.97; p=0.034), suggesting that combined PARP and AR inhibition may provide clinical benefit for a broad mCRPC population. [Clarke N, et al, ASCO GU 2023, abstract LBA16; Lancet Oncol 2018;19:975-986]

PROpel study
PROpel is a phase III, randomized, double-blind, placebo-controlled, multicentre study that evaluated the efficacy and safety of first-line olaparib (300 mg BID) plus abiraterone (1,000 mg QD) (n=399) vs placebo plus abiraterone (1,000 mg QD) (n=397) in patients with mCRPC. Patients in both treatment groups also received either prednisone or prednisolone (5 mg BID). Investigator-assessed rPFS was the primary endpoint, whereas OS was the key secondary endpoint. [NEJM Evid 2022;doi:10.1056/EVIDoa2200043]

“Although the patient population [in PROpel] is similar to that in COUAA-302 and PREVAIL, the control group in PROpel received an active treatment [ie, abiraterone],” Clarke noted. [Lancet Oncol2015;16:152-160; Euro Urol 2017;71:151-154; NEJM Evid 2022;doi:10.1056/EVIDoa2200043]

Baseline patient characteristics, including age (median, 69.0 years vs 70.0 years), prior docetaxel treatment at metastatic hormone-sensitive prostate cancer stage (22.6 percent vs 22.4 percent), site of metastasis (bone, 87.5 percent vs 85.4 percent; distant lymph nodes, 33.3 percent vs 30.0 percent), and HRRm status (HRRm, 27.8 percent vs 29.0 percent; non-HRRm, 69.9 percent vs 68.8 percent), were generally balanced between the two groups. [NEJM Evid 2022;doi:10.1056/ EVIDoa2200043; Clarke N, et al, ASCO GU 2023, abstract LBA16]

“Although patients enrolled in PROpel were not selected by HRRm status, this status was known in nearly 98 percent of patients, where patients without HRRm comprised approximately 70 percent of the trial’s population,” commented Clarke.

Initial efficacy results
At the planned primary analysis at the first data cut-off on 30 July 2021, abiraterone plus olaparib demonstrated a significantly longer median rPFS vs abiraterone plus placebo (24.8 months vs 16.6 months; HR, 0.66; 95 percent CI, 0.54–0.81; p<0.0001) in the intention-to-treat (ITT) population. This was consistent with the results of the blinded independent central review (27.6 months vs 16.4 months; HR, 0.61; 95 percent CI, 0.49–0.74, p<0.0001 [nominal]). [NEJM Evid 2022;doi:10.1056/EVIDoa2200043; Clarke N, et al, ASCO GU 2023, abstract LBA16]

At the first data cut-off, OS trend favoured abiraterone plus olaparib, although OS data were still immature (maturity, 28.6 percent; HR, 0.86; 95 percent CI, 0.66–1.12; p=0.29). [NEJM Evid 2022;doi:10.1056/EVIDoa2200043] A similar trend was shown in the second interim analysis (maturity, 40.1 percent; HR, 0.83; 95 percent CI, 0.66–1.03; p=0.11). [Ann Oncol 2022;33(Supp 7):S1160]

Final prespecified OS analysis results
The OS trend in favour of abiraterone plus olaparib was sustained at the third data cut-off on 12 October 2022. In the ITT population, median OS was 42.1 months for abiraterone plus olaparib vs  34.7 months for abiraterone plus placebo (maturity, 47.9 percent; HR, 0.81; 95 percent CI, 0.67–1.00, p=0.0544). (Figure 1) [Clarke N, et al, ASCO GU 2023, abstract LBA16]

“Median OS was >7 months [7.4 months] longer in the combination arm. This should be considered as a clinically meaningful survival advantage in the first-line mCRPC setting vs current SoC,” Clarke commented. “The OS trend observed at the final prespecified analysis was sustained beyond 42 months, which is the longest median OS reported to date in a phase III first-line mCRPC trial.” (Figure 1)

“The OS improvement associated with abiraterone plus olaparib was generally consistent across subgroups,” Clarke added. The median OS and corresponding HRs according to age, sites of metastases, prior docetaxel treatment, HRRm status, and BRCA mutation status all favoured the olaparib vs placebo group. (Figure 2)

Safety results
At the third data cut-off, the rate of any adverse events (AEs) was similar between groups, with no new safety signals. There were more AEs leading to dose interruptions or reductions and more cases of discontinuation in the olaparib vs placebo group. The most common grade ≥3 AE associated with abiraterone plus olaparib was anaemia (16.1 percent). “However, these AEs were generally manageable, and most occurred early after treatment initiation and resolved within 6 months,” said Clarke. (Figure 3) [Clarke N, et al, ASCO GU 2023, abstract LBA16]

In PROpel, the incidence of new primary malignancies (18 cases vs 14 cases) was similar between the two arms. In the olaparib arm, there were two cases of myelodysplastic syndrome/acute myeloid leukaemia. [Clarke N, et al, ASCO GU 2023, abstract LBA16]

“Health-related quality of life [QoL] findings were similar between treatment arms, based on total scores in the Functional Assessment of Cancer Therapy-Prostate [FACT-P] questionnaire. This means that adding olaparib to SoC abiraterone was not detrimental to patients’ QoL,” noted Clarke.

Conclusion
PROpel met its primary endpoint, demonstrating that adding olaparib (300 mg BID) to SoC abiraterone provided statistically significant and clinically meaningful rPFS benefits in patients with mCRPC. At the final prespecified analysis, a sustained trend of OS benefit was observed with abiraterone plus olaparib, with a 7.4-month improvement vs abiraterone. The median OS of 42.1 months is also the longest reported to date in a phase III trial on first-line mCRPC treatment. No new safety issues were reported, and AEs were generally manageable.

“Based on these findings, olaparib in combination with abiraterone represents an important new first-line treatment option for mCRPC,” concluded Clarke.