POTENTIAL COMBINATIONS WITH CDK 4/6 INHIBITORS
As with most cancer therapeutics, resistance develops with time; therefore, it is important to understand these mechanisms as they provide insight into which patients will respond and potential combination therapies to slow or overcome resistance. Multiple reviews have been published outlining CDK4/6i mechanisms of resistance in breast cancer.34 Potential mechanism of resistance include loss of Rb, upregulated CCNE1, activation of E2F, Cyclin E-CDK2 axis, driver mutations in PIK3CA, fibroblast growth factor axis and increasing 3-phosphoinositide-dependent protein kinase 1 (PDK1) and mitogen-activated protein kinase (MAPK) activation.34,35 In addition to mechanism of resistance, mechanism of action of CDK4/6 inhibitors are also important to guide combination therapy. CDK4/6 inhibitors’ mechanism of action is largely dependent on the Rb pathway; however, Rb independent effects are also present. These Rb independent pathways include CDK4/6 inhibitor effects on FOXM1 and SPOP;36 however, the impact of these Rb independent pathways is unclear since most patients with Rb loss have shown little activity to CDK4/6 inhibitors and is one of the main mechanisms of resistance.34 Guided by key pathways within PCa, PCa specific genomics and resistance profiles of CDK4/6i’s, we will review how CDK4/6i’s can be combined with agents from the following categories: chemotherapy, immunotherapy, DNA repair pathway, PI3K/AKT, FOXO3-FOXM1 axis, FGF-FGFR axis, Ras/Raf/MEK/ERK axis, and TP53 modulators.
In 2004, the US Food and Drug Administration (FDA) approved a taxane, docetaxel, for mCRPC based on its survival benefit.37 Subsequently, semisynthetic taxane cabazitaxel was first approved in 2010 for second-line treatment for mCRPC.38 Taxane’s mechanism of action includes inhibition of microtubular depolymerization arresting cells in G2/M phase of the cell cycle and attenuation of bcl-2 and bcl-xL gene expression promoting apoptosis.39 The ability to use cabazitaxel after docetaxel resistance is due to its poor affinity for P-glycoprotein efflux pumps which allows cabazitaxel to remain in the cell. Given the effects of taxanes on the cell cycle, these agents have been combined with CDK4/6i’s in various malignancies. However, the scheduling of these agents appears to affect the response. In preclinical breast cancer models, when the taxane paclitaxel was given concurrently with palbociclib it showed antagonism, but showed synergy when given sequentially via intermittent dosing.40,41 This finding can be explained by their mechanisms of action. When a CDK4/6i is administered it arrests cells in G1 which prevents cancer cells from eventually entering M phase, thereby, protecting cells from paclitaxel-induced cell death in M phase. When given sequentially it is hypothesized that G1 synchronization will occur after CDK4/6i is held, allowing more cells to enter M phase and enable cell death from paclitaxel.41 A Phase I trial with intermittent dosing in advanced breast cancer was performed and showed safety and tolerability.41 In PCa, a phase Ib/2 clinical trial is investigating ribociclib with docetaxel and prednisone in mCRPC patients with androgen signaling inhibitor resistance and no prior chemotherapy.42 Preliminary results of 14 patients showed PSA decrease by 50% or more in 29% of patients with neutropenia as the most commonly observed adverse event. Further trials in PCa with combining chemotherapy could be conducted, but dosing schedule should be considered.
Over the past decade, immunotherapy has taken the field of oncology by storm; however, in PCa the only FDA-approved autologous cellular immunotherapy is sipuleucel-T (Provenge).43 PCa has been unresponsive to immunotherapy which could be explained by its cold tumor environment as evident by a compromised cellular immunity and highly immune suppressive tumor microenvironment.44 CDK4/6i’s have been shown to enhance T-cell activation, increase T-cell tumor infiltration, and increase tumor expression of programmed death-ligand 1 (PD-L1) (Figure 2). 45,46 These changes support the potential synergistic effects with combining CDK4/6i’s and immunotherapy given the increased amount of immune cells in the tumor microenvironment and ability to block the immune suppressive effects of PD-L1. Inhibition of CDK4/6 increases PD-L1 protein by preventing cyclin D1-CDK4 phosphorylation of speckle-type POZ protein (SPOP), which without phosphorylation, compromises ubiquitination of PD-L1 that leads to PD-L1 protein degradation.46 High PD-L1 results in suppression of the host’s immune response to the cancer; however, this may make the tumor more vulnerable to immunotherapy. In PCa, cancer-derived SPOP mutations, seen in 8–15% of patients (Table 1),30,31,47,48 also increases PD-L1, but can cause decreased CD3+ tumor infiltrating lymphocytes and thus, leading to a cold tumor environment. This mutation resulted in increased growth of PCa xenografts compared to wild-type SPOP. Therefore, patients with SPOP mutations treated with CDK4/6i’s may be responsive to immunotherapy. In triple negative breast cancer mouse xenografts, combinations of CDK4/6i with a PI3K inhibitor and a PD-1 inhibitor induced complete and durable regressions.49 A clinical trial using CDK4/6i’s with immunotherapy is ongoing in various cancers. For example, abemaciclib plus pembrolizumab is currently being investigated in patients with metastatic breast cancer,50 and also in glioblastoma (NCT04118036), head and neck (NCT03938337), metastatic gastroesophageal (NCT03997448), and lung cancer (NCT02079636). There are no ongoing clinical trials in PCa using these class combinations; however, over 1000 clinical trials in PCa are investigating vaccines, immune checkpoint inhibitors, immunomodulators, adoptive cell transfer, and oncolytic virus-mediated immune response.44
DNA Repair Pathway
When DNA is damaged it relies on various pathways to undergo repair including: direct repair, mismatch repair (MMR), base excision repair (BER), nucleotide excision repair (NER) and double strand break (DSB) via non-homologous end joining and homologous recombination repair (HRR).51 Poly (adenosine diphosphate) [ADP]-ribose polymerases (PARP) are DNA repair enzymes involved in single stranded breaks and BER.52 When PARP is inhibited, single stranded breaks accumulate and lead to double stranded breaks which are repaired via HRR. However, aberrations within the HRR pathway, such as BRCA1/2 mutations, can result in synthetic lethality in the presence of PARP inhibitors (PARPi) (Figure 3).53 Therefore, patients with DNA repair aberrations (germline or somatic) are most sensitive to PARPi. DNA repair aberrations are seen in approximately 24% of patients with mCRPC.30 Specifically, BRCA2 loss of function alteration is seen between 5–13% of this cohort.30–32 In PCa xenografts, PARP-1 activity has been associated with progression to CRPC and PARP inhibition leads to delayed progression to CRPC, diminished androgen receptor function and reduced CRPC growth.54 In the TOPARP trial, a PARP inhibitor, olaparib, was used as a single agent in patients with heavily pretreated mCRPC and showed antitumor activity in patients with DNA damage response (DDR) gene aberrations, especially in BRCA1/2 alterations.55 Over 592 patients were screened for this trial and 27% of patients had DDR aberrations (7% BRCA2, 7% ATM, 6% CDK12, 7% other).55 The response evaluation criteria in solid tumors (RECIST) objective response rate based on these aberrations was 52.4%, 8.3%, and 0%, respectively; in addition, PSA was decreased by 50% or more in 76.7%, 5.3% and 0%, respectively.55 Of the 33 evaluated patients in the 400 mg olaparib cohort, a radiologic response was seen in 24.2%.55 Since this trial, two PARPi are now approved for use in mCRPC including rucaparib and Olaparib. Rucaparib gained FDA approval in 2020 for mCRPC patients with germline or somatic BRCA mutations who progressed on ADT and taxane-based chemotherapy. The TRITON2 trial showed rucaparib had an objective response rate (ORR) of 44% (11 of 25 patients) with 56% of these patients having a duration of response of ≥6 months.56 Also in 2020, olaparib gained approval for HRR gene-mutated mCRPC. In the PROfound trial,57 radiologic progression-free survival (rPFS) for olaparib was 7.4 months vs 3.6 months for patients treated with enzalutamide or abiraterone; median overall survival (mOS) was also improved, 19.1 months vs 14.7 months. The ORR was 33% vs 2%. These trials demonstrated that single agent PARP inhibitor can be used in PCa patients with HRR gene aberrations, but could combination therapy be used to improve responses? Multiple clinical trials are evaluating PARP inhibitors in combination with other agents such as androgen signaling inhibitors (NCT04179396) and immunotherapy (NCT03572478) in PCa patients with DNA damage alterations. Combination therapy with PARP inhibitors is also being investigated in patients with a proficient homologous recombination pathway. In vitro and in vivo ovarian cancer models, combining PARPi with CDK4/6i’s showed synergistic effects with palbociclib by inducing homologous recombination repair deficiency through downregulation of MYC regulated HR pathway genes leading to synthetic lethality with olaparib.58 Additionally, high MYC expression determined sensitivity to combination therapy.58 Since MYC amplifications occur in 20% of patients with mCRPC,30,32 combining these agents is a promising combination. PARP inhibitors also demonstrated effects on the FOXM1 transcription factor axis by inducing expression and nuclear localization of FOXM1 which in turn up regulates expression of genes involved in the homologous recombination (HR) pathway.59 When FOXM1 inhibited cells were treated with olaparib it resulted in increased DNA damage and PARP trapping. It has been demonstrated that CDK4/6i’s can decrease FOXM1,60 which could potentially circumvent the increase FOXM1 effects of PARPi. In clinical trials, olaparib, palbociclib and fulvestrant combination is being investigated in patients with BRCA-mutation-associated metastatic breast cancer (NCT03685331). No clinical trials are investigating PARPi +CDK4/6i in PCa.
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