Clinical Application of Poly(ADP-ribose) Polymerase (PARP) Inhibitors in Prostate Cancer
Abstract
:Simple Summary
Abstract
1. Introduction
2. PARP and PARP Inhibitors
3. PARP Inhibitors in Prostate Cancer
4. Phase II Clinical Trials of PARP Inhibitors in Prostate Cancer
Trial Name | Phase of Trial (n = Number of Patients) | Treatment Arms | Patient Population | HRR Biomarker Inclusion | Key Endpoints | Key Efficacy Results | Responses in Molecular Subtypes |
---|---|---|---|---|---|---|---|
Phase II PARP inhibitor single agent trials in metastatic castrate resistant prostate cancer after taxane therapy | |||||||
TOPARP-A [3] | Phase II (n = 50) | Olaparib 400 mg BD. | mCRPC, progressed after 1 or 2 taxane-based regimes. | Unselected; subsequent molecular characterization for HRR alterations. | PE: Composite response rate; radiological, PSA50 or CTC reduction. SE: rPFS, OS. | All patients: Composite response 33% (95% CI 20–48), PSA50 22%. | 88% composite response in HRR altered (BM+) cohort vs. 6% without HRR alterations (BM-) rPFS 9.8 (BM+) vs. 2.7 mo (BM-) (p < 0.001). Median OS 13.8 (BM+) vs. 7.5 mo (BM-) (p = 0.05). Composite response BRCA2: 100%, ATM: 80%. |
TOPARP-B [6] | Phase II (n = 98) | Olaparib 300 mg BD or 400 mg BD. | mCRPC progressed after 1 or 2 taxane-based regimes. | Biallelic deleterious HRR alterations. | PE: Composite response rate (defined as TOPARP-A) SE: rPFS, OS. | Composite response 400 mg: 54.3% (95% CI 39.0–69.1), 300 mg: 39.1% (25.1–54.6). Median rPFS 5.5 mo (95% CI 4.4–8.3) 400 mg vs. 5.6 mo (3.7–7.7) 300 mg. Median OS 14.3 mo (9.7–18.9) 400 mg vs. 10.1 mo (9.0–17.7) 300 mg. | Composite response BRCA1/2 83.3% (65.3–94.4), PALB2 57.1% (18.4–90.1), ATM 36.8% (16.3–61.6), CDK12 25% (8.7–49.1), Other 20% (5.7–43.7). |
TRITON 2 [8,9,34] | Phase II (n = 115 BRCA 78 non-BRCA) | Rucaparib 600 mg BD. | mCRPC, progressed after at least 1 taxane-based regimen and 1 ARPI. | Bi- or monoallelic, germline, or somatic deleterious BRCA1/2 mutation or other prespecified HRR gene. | PE: ORR SE: DOR, PSA50. | BRCA1/2 ORR 43.5% (95% CI 31.0–56.7), PSA50 54.8% (45.2–64.1). Median DOR not reached (NR; 95% CI 6.4 mo-NR), PSA50 54.8% (95% CI 45.2–64.1). | PSA50 gBRCA 61.7% (95% CI 46.4–75.5), sBRCA 50% (37.6–62.4). ORR gBRCA 45.8% (95% CI 25.6–67.2), sBRCA 42.1% (26.3–59.2). ATM: ORR 10.5%, PSA50 4.1%. CDK12: ORR 0%, PSA50 6.7%. CHEK12: ORR 11.1%, PSA50 16.7%. |
GALAHAD [5] | Phase II (n = 289) | Niraparib 300 mg OD. | mCRPC progressed after at least 1 taxane-based regimen and 1 ARPI. | Biallelic HRR or germline pathogenic BRCA1/2 alterations (BRCA cohort) or biallelic alterations in other prespecified DDR genes (non-BRCA cohort)—included ATM, BRIP1, CHEK2, FANCA, HDAC2, PALB2. | PE: ORR (trial amended PE) in BRCA cohort. SE: ORR in non-BRCA, OS, rPFS, composite response (radiological, PSA50 or CTC reduction). | ORR BRCA: 34.2% (95% CI 23.7–46.0). Non-BRCA: 10.6% (3.5–23.1). OS BRCA 13.01, non-BRCA 9.63 mo. rPFS BRCA 8.08, non-BRCA 3.71 mo. Composite response BRCA 58%, non-BRCA 15%. | Results for BRCA1 and BRCA2 cohorts reported together. |
TALAPRO 1 [35] | Phase II (n = 128) | Talazoparib 1 mg OD. | mCRPC progressed after at least 1 taxane-based regimen and 1 ARPI. | Mono- or biallelic HRR alterations (CDK12 excluded). | PE: ORR, SE: OS rPFS, PSA50. | ORR 29.8% (95% CI 21.2–39.6). Median OS 16.4 mo (95% CI 12.2–19.9). Median rPFS 5.6 mo (95% CI 3.7–8.8). PSA50 42% . | ORR: BRCA1/2 46%, BRCA2 46%, PALB2 25%, ATM 12%, Other 9%. |
Phase III PARP inhibitor single agent trials in metastatic castrate resistant prostate cancer | |||||||
PROfound [7] | Phase III (n = 387) | Olaparib 300 mg BD vs. physicians choice of enzalutamide or abiraterone. | mCRPC after at least 1 ARPI (previous taxane was allowed). | Bi- or monoallelic, somatic, or germline, deleterious HRR alterations. Cohort A: BRCA1/2 or ATM mutations. Cohort B: other 12 HRR genes mutations. | PE: rPFS in cohort A. SE: ORR, PSA50, OS. | Median rPFS Cohort A + B 5.8 olaparib vs. 3.5 mo control (HR 0.49 95% CI 0.38–0.63). ORR 22% olaparib vs. 4% control (OR 5.93; 95% CI 2.01–25.40). Median OS (prelim) 17.5 olaparib vs. 14.3 mo control (HR 0.67; 95% CI 0.49–0.93). PSA50 30% olaparib vs. 10% control. | Median PFS Cohort A: 7.4 olaparib vs. 3.6 mo control (HR 0.34; 95% CI 0.25–0.47). Cohort B: 5.8 mo vs. 3.5 mo (HR 0.49, 95% CI: 0.38–0.63). Cohort A: ORR 33% olaparib vs. 2% control (OR 20.86; 95% CI 4.18–379.18). Cohort A: PSA50 43% olaparib vs. 8% control. Cohort A: Median OS (prelim) 18.5 olaparib vs. 15.1 mo control (HR 0.64; 95% CI 0.43–0.97). |
TRITON3 [41] | Phase III (n = 405) | Rucaparib vs. physicians choice of either enzalutamide, abiraterone or docetaxel. | mCRPC progressed after ARPI (no prior chemotherapy in castrate resistant setting). | BRCA1/2 or ATM alteration. | PE: rPFS. SE: OS, ORR. | Prelim: ITT population (ATM and BRCA) Median rPFS 10.2 rucaparib vs. 6.4 mo control:HR 0.50 (95% CI 0.36–0.69). OS data immature. | Prelim: BRCA: Median rPFS 11.2 rucaparib vs. 6.4 mo control (p < 0.0001). ATM: Median rPFS 8.1 rucaparib vs. 6.8 mo control (p = 0.8421). OS data immature. |
5. Phase III Clinical Trials of PARP Inhibitors in Prostate Cancer
6. Targeting Androgen Receptor (AR) and PARP Concurrently
7. Biomarkers of Response and Resistance
8. BRCA and HRR Testing in Advanced Prostate Cancer
9. Combination Therapeutics with PARP Inhibitors
9.1. PARP Inhibition and Immunotherapy
9.2. PARP and Other Targeted Therapies
9.3. PARP and Radioligand Therapy
10. Conclusions and Future Directions
Author Contributions
Funding
Conflicts of Interest
References
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Trial Name | Phase of Trial (n = Number of Patients) | Treatment Arms | Patient Population | HRR Biomarker Inclusion | Key Endpoints | Key Efficacy Results |
---|---|---|---|---|---|---|
NCT01972217 [46] | Phase II (n = 142) | Olaparib plus abiraterone vs. placebo and abiraterone. | mCRPC following prior docetaxel. | Unselected. | PE: rPFS. SE: PFS 2, OS. | rPFS 13.8 olaparib vs. 8.2 mo placebo (HR 0.65; 95% CI 0.44–0.97; p = 0.034). Median PFS2 23.3 (95% CI 17.4—not reached) olaparib vs. 18.5 mo (16.1–23.8) placebo (HR 0.79; 95% CI 0.51–1.21; p = 0.28). Median OS 22.7 (95% CI 17.4–29.4) olaparib vs. 20.9 mo (17.6–26.3) placebo (HR 0.91; 95% CI 0.60–1.38; p = 0.66). |
TALAPRO-2 [49] | Phase III (n = 1095) | Talazoparib plus enzalutamide vs. placebo and enzalutamide. | mCRPC, first-line (ARPI allowed in the castration sensitive setting). | Cohort 1: HRR unselected. Cohort 2: selected for HRR gene alterations. | PE: rPFS. SE: OS. | Prelim: rPFS benefit with talazoparib combination exceeded prespecified HR 0.696. |
PROpel [47] | Phase III (n = 796) | Olapaib plus abiraterone and prednisolone vs. placebo abiraterone and prednisolone. | mCRPC, first-line (study allowed for prior treatment with docetaxel in the first-line hormone sensitive setting). | Unselected | PE: rPFS. SE: OS. | Prelim: rPFS 24.8 olaparib and abiraterone vs. 16.6 mo (HR 0.66, 0.95% CI 0.54–0.81; p < 0.0001). HRRm cohort: median rPFS 28.8 olaparib and abiraterone vs. 13.8 mo (HR 0.45; 95% CI 0.31–0.65). Non-HRRm cohort: median rPFS 27.6 olaparib and abiraterone vs. 19.1 mo (HR 0.72; 95% CI 0.56–0.93). Cohort with BRCA alterations: median rPFS NR olaparib and abiraterone vs. 8.4 mo (HR 0.18; 95% CI 0.09–0.34). Cohort without BRCA alterations: median rPFS 27.6 olaparib and abiraterone vs. 16.6 mo (HR 0.72; 95% CI 0.58–0.90). OS data immature. |
CASPAR [51] | Phase III (n = 984) | Rucaparib plus enzalutamide vs. placebo and enzalutamide. | mCRPC treatment-naïve. | Unselected. | PE: rPFS, OS. SE: rPFS in BRCA1/2 and PALB2. | Ongoing. |
MAGNITUDE [48] | Phase III (n = 670) | Niraparib plus abiraterone vs. placebo and abiraterone. | mCRPC treatment-naïve (allowed for patients who had received less than four months prior abiraterone therapy). | Cohort without HRR alterations and HRR altered cohort (BM+): ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, PALB2. | PE: rPFS in BRCA1/2 alterations and BM+ cohort. SE: OS. | Prelim: rPFS in BRCA1/2: 16.6 vs. 10.9 mo (HR 0.53 95%CI 0.36–0.79); p = 0.0014). rPFS in BM+ cohort 16.5 vs. 13.7 mo (HR 0.73 95% CI 0.56–0.96); p = 0.0217). |
TALAPRO-3 [52] | Phase III (n = 550) | Talazoparib plus enzalutamide vs. placebo and enzalutamide. | mHSPC. | Selected for alterations in ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C. | PE: rPFS. SE: OS. | Ongoing. |
AMPLITUDE [53] | Phase III (n = 788) | Niraparib plus abiraterone vs. placebo and abiraterone. | mHSPC (allowed less than 6 months of ADT prior to randomisation and <3 y total). | Selected for HRR gene alteration. | PE: rPFS. SE: OS. | Ongoing. |
TRAP [78] | Phase II (n = 47) | Ceralasertib (AZD 6738; ATR inhibitor) plus olaparib. | Multiple solid organ malignancies, includes mCRPC cohort with previous ARPI (n = 10). | Cohort 1 with and Cohort 2 without HRR alterations. | PE: Composite response (radiological or PSA50) SE: PFS. | Prelim: Cohort 1 (HRR alterations): PSA50 40%. |
NCT03840200 [82] | Phase Ib (n = 51) | Ipatasertib (AKT inhibitor) plus rucaparib. | Breast, ovarian, or prostate cancer: including progressive mCRPC with prior ARPI. | Unselected. | Key PE: PSA50, dose-limiting toxicities, recommended phase II dose. SE: ORR, rPFS. | Prelim: PSA50 22% all mCRPC patients, 50% in HRR alterations, 25% without HRR alterations. ORR 4% all patients. |
NCT02893917 [84] | Phase II (n = 90) | Cediranib plus olaparib (Arm A) or olaparib alone (Arm B). | mCRPC ≥ 1 prior line of therapy. | Unselected. | PE: rPFS. SE: ORR, PSA50. | Median rPFS 8.5 Arm A vs. 4.0 mo (HR 0.617, 95% CI 0.392–0.969 = 0.0359). ORR 19% Arm A vs. 12%. |
NCT02484404 [70] | Phase I/II (n = 384) | Durvalumab plus olaparib and/or cediranib. | mCRPC previously treated with ARPI. | Unselected. | PE: clinical efficacy. SE: ORR, PSA50. | Radiographic and/or PSA response in 53%. All patients: 12-month rPFS 51.5%. Median rPFS for cohort with HRR alterations: 16.1 mo. |
REPAIR [86] | Phase I (n = 48) | Pidnarulex (CX-5461) plus talazoparib. | mCRPC prior taxane, and ARPI. | Unselected. | PE: maximum tolerated dose. SE: PSA50, rPFS, ORR, OS. | Ongoing. |
NCT03810105 [91] | Phase II (n = 5) | Olaparib plus durvalumab. | Castration sensitive biochemically recurrent nonmetastatic prostate cancer. | HRR deleterious mutations. | PE: undetectable PSA. | Ongoing. |
KEYNOTE-365 [71] | Phase Ib/2 (Cohort A n = 84) | Olaparib with pembrolizumab. | Cohort A: mCRPC post docetaxel, up to 2 prior ARPI. | Unselected. | Key PE: PSA50 ORR. SE: OS, rPFS. | Prelim: PSA50 9%. ORR 8%. OS 14 mo. |
KEYLYNK-010 [72] | Phase III (n = 793) | Olaparib with pembrolizumab vs. ARPI. | mCRPC progressed with prior ARPI and docetaxel. | Unselected. | PE: rPFS and OS. SE: ORR. | Stopped for futility in 2022. Median rPFS 4.4 pembrolizumab and olaparib vs. 4.2 mo ARPI (HR 1.02; 95% CI 0.82–1.25). OS 15.8 pembrolizumab and olaparib vs. 14.6 mo (HR 0.94; 95% CI 0.77–1.14) ORR 17% vs. 6% ARPI (p = 0.002). |
CheckMate 9KD [73] | Phase II (n = 81 cohort A1) | Nivolumab combined with rucaparib (Arm A), docetaxel (Arm B) or enzalutamide (Arm C). | mCRPC (Arm A1: post 1–2 prior taxane regimes ≤ 2 ARPIs). | Unselected. | PE: ORR, PSA50. SE: rPFS, OS. | Cohort A1: ORR 10.3%, all, 17.2% HRR alterations, 3.4% without. PSA50 11.9% all, 18.2% HRR alterations, 5% without. All patients in cohort A1: Median rPFS 4.9 mo. Median OS 13.9 mo. |
QUEST [74] | Phase II (n = 136) | Niraparib with abiraterone plus cetrelimab. | mCRPC. | Unselected. | Key PE: ORR, composite response (radiological, CTC, or PSA50 response). SE: OS. | Ongoing. |
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Inderjeeth, A.-J.; Topp, M.; Sanij, E.; Castro, E.; Sandhu, S. Clinical Application of Poly(ADP-ribose) Polymerase (PARP) Inhibitors in Prostate Cancer. Cancers 2022, 14, 5922. https://doi.org/10.3390/cancers14235922
Inderjeeth A-J, Topp M, Sanij E, Castro E, Sandhu S. Clinical Application of Poly(ADP-ribose) Polymerase (PARP) Inhibitors in Prostate Cancer. Cancers. 2022; 14(23):5922. https://doi.org/10.3390/cancers14235922
Chicago/Turabian StyleInderjeeth, Andrisha-Jade, Monique Topp, Elaine Sanij, Elena Castro, and Shahneen Sandhu. 2022. "Clinical Application of Poly(ADP-ribose) Polymerase (PARP) Inhibitors in Prostate Cancer" Cancers 14, no. 23: 5922. https://doi.org/10.3390/cancers14235922