Radiotherapy and, more recently, PARP inhibitors (PARPis) and immune-checkpoint inhibitors represent effective tools in cancer therapy. Radiotherapy exerts its effects not only by damaging DNA and inducing tumor cell death, but also stimulating anti-tumor immune responses. PARPis are known to exert their therapeutic effects by inhibiting DNA repair, and they may be used in combination with radiotherapy. Both radiotherapy and PARPis modulate inflammatory signals and stimulate type I IFN (IFN-I)-dependent immune activation. However, they can also support the development of an immunosuppressive tumor environment and upregulate PD-L1 expression on tumor cells. When provided as monotherapy, immune-checkpoint inhibitors (mainly antibodies to CTLA-4 and the PD-1/PD-L1 axis) result particularly effective only in immunogenic tumors. Combinations of immunotherapy with therapies that favor priming of the immune response to tumor-associated antigens are, therefore, suitable strategies. The widely explored association of radiotherapy and immunotherapy has confirmed this benefit for several cancers. Association with PARPis has also been investigated in clinical trials. Immunotherapy counteracts the immunosuppressive effects of radiotherapy and/or PARPis and synergies with their immunological effects, promoting and unleashing immune responses toward primary and metastatic lesions (abscopal effect).
Radiotherapy plays a major role in the treatment of a wide range of malignancies. Around 60–70% of patients undergo treatments, mostly with photon therapy (X- or γ-rays), in addition to others with heavy ions and protons.
Ionizing radiations (IRs) induce DNA damage with the number, distribution, variety, and severity of lesions depending on the quality of radiation, dose, fractionation, cell physiological status, and tumor microenvironment (TME) (including oxygen availability). DNA damage is induced by direct energy deposition or indirectly through the generation of highly reactive free radicals. Lesions induced by a single ionizing trajectory localize within short distances (nanometers); these clustered lesions are a typical signature of IR-damaged DNA [1][2]. The large number of clustered DNA lesions, including multiple double-strand breaks, generated by IR are hardly fixed by the DNA repair mechanisms and lead to cell-cycle arrest and/or cell death [3]. While radiation toxicity has been considered the (main) mechanism of action in radiotherapy, its collateral tissue damage has urged more favorable ratios between the dose adsorbed by the targeted tumor and the normal tissues. Both three-dimensional conformal and intensity-modulated RT reduced nontargeted tissue toxicity and improved overall survival compared with two-dimensional RT, although with some contrasting conclusions [4][5]. A better dose distribution on the targeted tissue compared with photon RT can be obtained with charged particles. While traveling through tissues, protons and carbon ions, the most used charged particles for RT, release energy according to a typical curve ending with a pronounced peak (Bragg peak). At the Bragg peak, the majority of the energy is released (with a tiny lateral scatter) and a massive ionization of the surrounding matter occurs. Tissues lying beyond the Bragg peak are, therefore, spared. Superimposition of multiple Bragg peaks spanning the tumor volume improves disease control [6].PARP-1, the most abundant member of the poly(ADP-ribose) (PAR) polymerase (PARP) family, more recently defined as diphtheria toxin-like ADP-ribosyltransferases (ARTDs), accounts for the majority of PARylation activity and has a high DNA damage-sensing ability [40]. Free DNA ends activate PARP-1, which highly PARylates itself and detaches from chromatin. Indeed, addition of PARs radically changes the electric charge of the targeted molecule, rendering it highly negative. As a consequence, PARylated proteins are electrostatically repulsed by the DNA, a mechanism involved in chromatin accessibility to DNA repair enzymes (and to DNA transcription and replication regulators). PARP-1 also generates large amounts of PARs that work as scaffolds recruiting DNA repair enzymes to the lesion site, including XRCC1 [41]. PARP-1 plays a central role in orchestrating responses to genotoxic stress and represents a critical enzyme in single-strand break and alternative end-joining repair [42][43]. However, recent studies also indicated that PARP-1 plays a role in double-strand break (DSB) repair mechanisms, including homologous recombination and classical nonhomologous end-joining (c-NHEJ) [44][45].
Following a long period of preclinical and clinical studies, PARP inhibitors (PARPis) reached wide clinical use with the approval of olaparib (AZD-2281) in 2014 and later on of niraparib (MK-4827), rucaparib (AG-014699), talazoparib (BMN673), and veliparib (ABT888) for treatment of ovarian, breast, prostate, and pancreatic cancer [46][47]. PARPis are the first clinically approved drugs exploiting synthetic lethality; that is, they target a function specifically vital in mutation-bearing cancer cells [48][49]. PARPis were shown to be lethal in homologous recombination (HR)-deficient BRCA1/BRCA2-mutated cancers, likely because collapsed replication forks are no longer repaired [50][51]. However, recent preclinical and early clinical studies also sustained the use of PARPis in other molecular subsets of cancer, including cancers with high replication stress [52].
All clinically approved PARPis share a nicotinamide-based moiety that inhibits PARP-1 enzymatic activity by competing for binding to the catalytic site with NAD. PARPis prevent PARP-1 auto-PARylation and its consequent removal from chromatin and DNA lesions. This effect, termed PARP trapping, is currently the preferred interpretative model of the PARPis mechanism of action. Indeed, cytotoxicity due to PARP correlates with the ability to trap PARP on DNA lesions and is more cytotoxic than gene deletion. PARP trapping leads to replication fork collapse during the S phase and consequent cell death [53][54].
As described above RT, PARPis and ICI have a certain therapeutic success when used alone but it is their combination that can result in a better and prolonged disease control. RT and PARPis synergize in inducing DNA damage and tumor cell death. They also induce immune stimulating factors potentially generating an immunogenic microenvironment and favoring immune infiltration. However, they also activate immune suppressive mechanisms and indeed the induction of a systemic immune response with abscopal effects remains uncommon and/or limited. On the other hand, ICIs can lower the threshold for immune activation, reinvigorate exhausted T cells, and dampen the action of regulatory T cells, consequently sustaining systemic immune responses and abscopal effect. Nevertheless, to be effective ICIs require a TME that allows priming of immune responses to tumor-associated antigens and tumor infiltration by leukocytes. Combinations of immunotherapy with therapies that favor priming of immune responses, such as RT, obtained important therapeutic success in clinical studies, with protocols including different forms of RT and ICI having been approved for several (advanced) cancers. Also the more recent association of PARPis and ICIs showed some clinical benefits. Altogether these results and the considerations expressed above encourage the use of combined therapies that include RT, PARPis and ICIs.
Promising results from initial studies in experimental models confirmed that the triple combination of RT, PARPis and ICI improve tumor infiltrate, and prime and unleash anti-tumor, T-cell-mediated, immune responses in mouse models [115][116][112][194]. Several phase I to III clinical trials, aimed at exploring different combinations of radiotherapy, PARPis and ICIs, included at least one arm with the concomitant or sequential use of these three therapeutic agents (often in addition to standard chemo-therapy). The effects of PARPis together with RT and ICI, targeting either CTLA-4 or PD-1/PD-L1 or both pathways, will be assessed in NSCLC, SCLC, breast, prostate, pancreatic, gastroesophageal, rectal, head and neck carcinomas. Many of these trials are still recruiting or not yet active. A wealthy of results will be available on these promising therapeutic combinations in forthcoming years [see Table 1 in Rosado et al, Cancers 2023, 15(Table 14), [117]1093].
Title | Conditions | Therapies | Phase | Estimated Enrollment (Patients) |
Status | Estimated Completion Dates | NCT Number | Last Update Posted |
---|---|---|---|---|---|---|---|---|
Testing the safety of the anticancer drugs durvalumab and olaparib during radiation therapy for locally advanced unresectable pancreatic cancer | Locally advanced pancreatic carcinoma Stage II or III pancreatic cancer Unresectable pancreatic carcinoma |
Durvalumab Olaparib RT |
I | 18 | Recruiting | Primary and final: 31 March 2024 | 05411094 | 1 December 2022 |
A safety study adding niraparib and dostarlimab to radiation therapy for rectal cancers | Rectal neoplasms Rectal neoplasm malignant |
Niraparib Dostarlimab Short course RT |
I–II | 38 | Recruiting | Primary: 31 December 2024 Final: 31 December 2026 |
04926324 | 26 July 2022 |
Niraparib + dostarlimab + RT in pancreatic cancer | Pancreatic cancer Metastatic pancreatic cancer |
Niraparib Dostarlimab RT |
II | 25 | Active, not recruiting |
Primary: 19 January 2022 Final: October 2026 |
04409002 | 8 September 2022 |
Radiation, immunotherapy, and PARP inhibitor in triple-negative breast cancer | Breast cancer TNBC |
Niraparib Dostarlimab RT |
II | 32 | Recruiting | Primary: 1 April 2023 Final: 1 December 2029 |
04837209 | 23 December 2022 |
Radiotherapy and durvalumab/durvalumab combo (tremelimumab/olaparid) for small-cell lung cancer | SCLC extensive stage SCLC |
Durvalumab Tremelimumab Olaparib Thoracic RT |
I | 25 | Active, not recruiting |
Primary and final: 1 June 2023 | 03923270 | 6 January 2023 |
A study of radiation therapy with pembrolizumab and olaparib or other radiosensitizers in women who have triple-negative or hormone-receptor positive/HER2 negative breast cancer | TNBC Metastatic breast cancer |
Pembrolizumab Olaparib RT |
II | 34 | Recruiting | Primary and final: January 2025 | 04683679 | 21 October 2022 |
Pembro with radiation with or without olaparib | Prostate cancer | Pembrolizumab Olaparib Androgen deprivation therapy RT |
II | 64 | Not yet recruiting |
Primary: 2 January 2025 Final: 2 January 2028 |
05568550 | 5 October 2022 |
Olaparib and durvalumab with carboplatin, etoposide, and/or radiation therapy for the treatment of extensive-stage small-cell lung cancer, PRIO trial |
Extensive-stage SCLC Stage IV lung cancer Stage IVA lung cancer Stage IVB lung cancer |
Carboplatin Durvalumab Etoposide Olaparib RT |
I–II | 63 | Recruiting | Primary and final: 31 January 2024 | 04728230 | 9 November 2022 |
Study of SBRT/olaparib followed by pembrolizumab/olaparib in gastric cancers | Gastric cancer Gastroesophageal cancer |
Pembrolizumab Olaparib SBRT |
II | 26 | Recruiting | Primary: December 2025 Final: December 2028 |
05379972 | 5 January 2023 |
Placebo-controlled study of concurrent chemoradiation therapy with pembrolizumab followed by pembrolizumab and olaparib in newly diagnosed treatment-naïve limited-stage small-cell lung cancer (LS-SCLC) (MK 7339-013/KEYLYNK-013) | SCLC | Pembrolizumab (2 doses) Olaparib Etoposide Platinum Standard thoracic RT Prophylactic cranial irradiation |
III | 672 | Recruiting | Primary and final: 28 October 2027 | 04624204 | 23 December 2022 |
Pembrolizumab plus olaparib in LA-HNSCC | Head and neck squamous cell carcinoma | Pembrolizumab Olaparib Cisplatin IMRT |
II | 45 | Recruiting | Primary: 31 October 2024 Final: 31 October 2025 |
05366166 | 28 October 2022 |
Study of pembrolizumab with concurrent chemoradiation therapy, followed by pembrolizumab with or without olaparib in stage III non-small-cell lung cancer (NSCLC) (MK-7339-012/KEYLYNK-012) | Lung neoplasms NSCLC |
Pembrolizumab Olaparib Etoposide Carboplatin Cisplatin Paclitaxel Pemetrexed Thoracic RT Durvalumab |
III | 870 | Recruiting | Primary and final: 6 July 2026 | 04380636 | 30 November 2022 |