A number of studies are investigating comparative monotherapy, combinations of PARP inhibitors and established therapies. In addition, niraparib and talazoparib are in late-stage development in combination therapy.
The many biological functions of PARPs underscore the rationale for using PARP inhibitors as combination partners with other agents.[1,2,3,4] Further, three general hypotheses underlie the rationale for the main combination strategies:
- Androgen receptor signalling regulates expression of DNA repair genes in prostate cancer,[5] so combination of PARP inhibition and androgen receptor-targeted therapy can further reduce DNA repair competency
- Increase DNA damage (e.g., with radiotherapy, radiopharmaceuticals or platinum-based chemotherapy) to enhance the potency of PARP inhibitors
- Induce antitumor immune response via cytotoxic compounds causing additional DNA damage and cell death and release of neoantigens
Ongoing phase III studies of the approved and investigational (in prostate cancer) PARP inhibitors are included below. In earlier-stage development, strategies investigating sequencing or synergistic effects of therapies with different mechanisms of action (to improve efficacy or address potential resistance) are underway.
References
[1] O'Connor MJ. Targeting the DNA damage response in cancer. Mol Cell. 2015 Nov 19;60: 547-560.
[2] Pearl LH, Schierz AC, Ward SE, et al. Therapeutic opportunities within the DNA damage response. Nat Rev Cancer. 2015 Mar;15:166-180.
[3] Gourley C, Balmana J, Ledermann JA, et al. Moving from PARP Inhibition to Targeting DNA Repair and DNA Damage Response in Cancer Therapy. J Clin Oncol. 2019 Sep 1;37(25):2257-2269.
[4] Jubin T, Kadam A, Jariwala M, et al. The PARP family: insights into functional aspects of poly (ADP-ribose) polymerase-1 in cell growth and survival. Cell Prolif. 2016; 49: 421-437.
[5] Polkinghorn WR, Parker JS, Lee MX, et al. Androgen receptor signaling regulates DNA repair in prostate cancers. Cancer Discov. 2013 Nov;3(11):1245-1253.
Key efficacy data from trials of PARP inhibitors in prostate cancer
More information on the clinical trials can be found by clicking on the links in the table
Monotherapy comparing with standard of care
Study: TRITON3
(NCT02975934 )
Phase III
Treatment line: 2L
Treatment arms: Rucaparib vs Physician’s choice of abiraterone, enzalutamide, or docetaxel
Patient population:
- mCRPC
- Homologous recombination gene deficiency
Estimated completion date/status: Feb-22
Combination therapy with ARSi
Study: PROpel
(NCT03732820 )
Phase III
Treatment line: 1L
Treatment arms: Olaparib plus abiraterone acetate vs Placebo plus abiraterone acetate
Patient population:
- mCRPC
- Unselected patients
Estimated completion date/status: June 11, 2021
Study: CASPAR
(NCT04455750 )
Phase III
Treatment line: 1L
Treatment arms: Rucaparib plus enzalutamide vs Enzalutamide
Patient population:
- mCRPC
- Unselected patients
Estimated completion date/status: Recruiting
Study: MAGNITUDE
(NCT03748641 )
Phase III
Treatment line: 1L
Treatment arms: Niraparib plus abiraterone acetate vs Placebo plus abiraterone acetate
Patient population:
- mCRPC
- Unselected patients stratified by HRR gene alteration (yes vs no)
Estimated completion date/status: July 21, 2022
Study: AMPLITUDE
(NCT04497844 )
Phase III
Treatment line: 2L
Treatment arms: Niraparib plus abiraterone acetate vs Placebo plus abiraterone acetate
Patient population:
- mCSPC
- Deleterious germline or somatic HRR gene-mutated
Estimated completion date/status: November 15, 2024
Study: TALAPRO-2
(NCT03395197 )
Phase III
Treatment line: 1L
Treatment arms: Talazoparib plus enzalutamide vs Enzalutamide plus placebo
Patient population:
- mCRPC
- Unselected patients
Estimated completion date/status: August 22, 2021
Study: TALAPRO-3
(NCT04821622 )
Phase III
Treatment line: 2L
Treatment arms: Talazoparib plus enzalutamide vs Enzalutamide plus placebo
Patient population:
- mCSPC
- DDR gene-mutated
Estimated completion date/status: Recruiting
Combination with radiopharmaceuticals
Study: LuPARP
(NCT03874884 )
Phase I
Treatment line: 2L
Treatment arms: Olaparib plus 177Lu-PSMA
Patient population:
- mCRPC
- Unselected patients
Estimated completion date/status: Apr-22
Treatment sequencing with platinum-based chemotherapy
Study: PLATI-PARP
(NCT03442556 )
Phase II
Treatment line: 2+L
Treatment arms: Rucaparib (maintenance) after induction therapy with docetaxel with carboplatin
Patient population:
- mCRPC
- Homologous recombination DNA repair deficiency
Estimated completion date/status: May 15, 2025
Study: PLATPARP
(NCT04288687 )
Phase II
Treatment line: 2L
Treatment arms: Niraparib after platinum-based chemotherapy
Patient population:
- CRPC
- DNA repair defects
Estimated completion date/status: Jun-22
1L, first-line; 2L, second-line; ARSi, androgen receptor-signalling inhibitor; CRPC, castration-resistant prostate cancer; DDR, DNA damage repair; HRR, homologous recombination repair; mCRPC, metastatic castration-resistant prostate cancer; mCSPC, metastatic castration-sensitive prostate cancer.