Clinical Development of PARP Inhibitors in Treating Metastatic Castration-Resistant Prostate Cancer
Abstract
:1. Introduction
2. Current Food and Drug Administration-Approved PARP Inhibitors
3. PARPi as Monotherapy for Metastatic Prostate Cancer
4. PARPi Combinations for Treating Metastatic Prostate Cancer
5. Future Directions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Drug (Manufacturer) | Structure | Oral Dosage | Half-Life | Metabolism | PARP Trapping Potency (1–5; 1 = Most Potent) |
---|---|---|---|---|---|
Olaparib (AstraZeneca) | 300 mg; twice a day | 11.9 h | Hepatic CYP3A4 | 4 | |
Rucaparib (Clovis Oncology) | 600 mg; twice a day | 18 h | Hepatic CYP2D6 | 3 | |
Niraparib (Tesaro) | 300 mg; daily | 36 h | Carboxylesterases | 2 | |
Veliparib (AbbVie) | 300 mg; twice daily | 6.1 h | Hepatic CYP2D6 | 5 | |
Talazoparib (Pfizer) | 1 mg; daily | 90 h | Hepatic mono-oxidation, dehydrogenation, cysteine conjugation of a mono-desfluoro metabolite, and glucuronide conjugation | 1 |
Study Name (NCT #) | Patient Population | Sample Size/Number of Pts | Study Design | PSA Response Rate | PFS (If Available) | Dosage | Reference |
---|---|---|---|---|---|---|---|
Monotherapy | |||||||
TOPARP-B (NCT01682772) | mCRPC progression on abiraterone, enzalutamide, docetaxel, or cabazitaxel | 49 (16 with DDR mutations) | olaparib | 100% of BRCA2 and FANCA mutated mCRPC drop ≥50% baseline | median PFS, 9.8 vs. 2.7 months; p < 0.001 | 400 mg twice a day | Mateo J et al., [22] |
TRITON2 (NCT02952534) | mCRPC and a DDR mutation previously been treated with abiraterone, enzalutamide, docetaxel, or cabazitaxel | 52 (23 BRCA-mutated) | rucaparib | 47.8% of BRCA-mutated; 95% CI, 26.8–69.4) | Not reported | 600 mg twice a day | Abida W et al., [23] |
GALAHAD (NCT02854436) | mCRPC patients with DDR mutations and progression on a taxane or androgen-receptor signaling inhibitor | 39 | niraparib | 57% (95% CI, 34–77) | Not reported | 300 mg once a day | Smith MR et al., [24] |
Combination Therapy | |||||||
NCT01085422 | mCRPC | 26 | Veliparib and temozolomide | 8.0% (95% CI, 1.0–26.0) | 9 weeks (95% CI, 8–17) | 40 mg twice a day and 150–200 mg once a day | Hussain M et al., [25] |
NCT01576172 | mCRPC | 148 (76 on abiraterone + veliparib | abiraterone versus abiraterone and veliparib | 72.4% | 10.1 versus 11 months (p = 0.95) | 1000 mg once a day and 40 mg twice a day | Hussain M et al., [26] |
NCT01972217 | mCRPC previously treated with docetaxel or cabazitaxel | 142 (71 on the olaparib + abiraterone arm) | abiraterone versus abiraterone and olaparib | Not reported | 8.2 versus 13.8 months (p = 0.034) | 1000 mg once a day and 300 mg twice a day | Clarke N et al., [27] |
cohort A of Keynote-365 (NCT02861573) | mCRPC previously treated with docetaxel or ≤2 androgen-receptor signaling inhibitors | 41 | Pembrolizumab and olaparib | 13% of patients had ≥50% PSA decline | 5 months (95% CI, 4–8) | 200 mg every 21 days and 400 mg twice a day | Yu EY et al., [28] |
NCT03810105 | mCRPC previously treated with enzalutamide or abiraterone | 17 | durvalumab and olaparib | 53% of patients had a radiographic response and ≥50% PSA decline | 16.1 months (95% CI, 4.5–16.1) | 1500 mg every 28 days and 300 mg twice a day | Karzai F et al., [29] |
Study Name (NCT Number) | Phase | Patient Population | Study Design | Primary Endpoint |
---|---|---|---|---|
Monotherapy | ||||
TALAPRO-1 (NCT03148795) | Phase II | DDR-mutated mCRPC progressed on a taxane or androgen-receptor signaling inhibitor | talazoparib | Objective Response Rate |
ROAR (NCT03533946) | Phase II | DDR-mutated mCRPC | rucaparib | PSA decline ≥50% rate |
Galahad (NCT02854436) | Phase II | DDR-mutated mCRPC who progressed on an androgen-receptor signaling inhibitor and taxane-chemotherapy | niraparib | Objective response rate |
TRITON3 (NCT02975934) | Phase III | germline or somatic BRCA1, BRCA2, or ATM mutations and mCRPC who previously progressed on an androgen-receptor signaling inhibitor and who have not received chemotherapy | rucaparib versus abiraterone, enzalutamide, or docetaxel | Progression-free survival |
PROfound (NCT02987543) | Phase III | mCRPC who progressed on an androgen-receptor signaling inhibitor | olaparib versus enzalutamide or abiraterone in patients with DDR-mutated | Progression-free survival |
Combination Therapy | ||||
PROpel (NCT03732820) | Phase III | mCRPC who have not received taxane-chemotherapy or an androgen-receptor signaling inhibitor | abiraterone and olaparib versus abiraterone and placebo | Progression-free survival |
BRCAaway (NCT03012321) | Phase II | DDR-mutated mCRPC | Abiraterone versus olaparib and abiraterone versus olaparib | Progression-free survival |
TALAPRO-2 (NCT03395197) | Phase III | asymptomatic or mildly symptomatic mCRPC, without brain metastases, never having received taxane-chemotherapy or an androgen-receptor signaling inhibitor | enzalutamide and talazoparib versus enzalutamide and placebo (prestratify based on DDR mutaton status) | Progression-free survival |
MAGNITUDE (NCT03748641) | Phase III | treatment naïve mCRPC | niraparib and abiraterone versus abiraterone and placebo | Progression-free survival |
KEYLINK-010 (NCT03834519) | Phase III | mCRPC progressed on an androgen-receptor signaling inhibitor | pembrolizumab and olaparib versus enzalutamide or abiraterone | Progression-free survival and Overall survival |
NCT03317392 | Phase I/Phase II | mCRPC with any number of bone metastases | olaparib and radium-223 | Progression-free survival |
NCT02893917 | Phase II | mCRPC who progressed on one prior line of therapy | olaparib versus olaparib and cediranib | Progression-free survival |
NCT03572478 | Phase I/Phase IIa | mCRPC who progressed on an androgen-receptor signaling inhibitor | rucaparib and nivolumab | Dose limiting toxicity |
NCT03516812 | Phase II | mCRPC who progressed on an androgen-receptor signaling inhibitor | olaparib and testosterone injection | PSA decline ≥50% rate |
NCT03810105 | Phase II | DDR-mutated mCRPC | olaparib and durvalumab | Number of patients with undetectable PSA |
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Adashek, J.J.; Jain, R.K.; Zhang, J. Clinical Development of PARP Inhibitors in Treating Metastatic Castration-Resistant Prostate Cancer. Cells 2019, 8, 860. https://doi.org/10.3390/cells8080860
Adashek JJ, Jain RK, Zhang J. Clinical Development of PARP Inhibitors in Treating Metastatic Castration-Resistant Prostate Cancer. Cells. 2019; 8(8):860. https://doi.org/10.3390/cells8080860
Chicago/Turabian StyleAdashek, Jacob J., Rohit K. Jain, and Jingsong Zhang. 2019. "Clinical Development of PARP Inhibitors in Treating Metastatic Castration-Resistant Prostate Cancer" Cells 8, no. 8: 860. https://doi.org/10.3390/cells8080860