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Professor of Medicine
B.J. Kennedy Chair in Clinical Medical Oncology
Director, Division of Hematology, Oncology and Transplantation
Department of Medicine
University of Minnesota
Division of Hematology, Oncology and Transplantation
University of Minnesota Health Clinics and Surgery Center
Charles J. Ryan, MD, has disclosed that he has research support from Bayer, Clovis, and Sanofi/Genzyme and consulting fees from Advanced Accelerator Applications, Bayer, Dendreon, Pfizer, and Roivant.
Mutations in DNA repair genes occur in approximately 12% of patients with metastatic prostate cancer. Single-agent PARP inhibition has demonstrated efficacy in metastatic castration-resistant prostate cancer with mutations in BRCA1/2. The goals of combining PARP inhibitors with other types of therapeutic agents are to improve the benefit derived from PARP inhibition and to increase the number of patients who may benefit from PARP inhibition. One challenge with combining PARP inhibitors with other therapies is defining the optimal target population for the different combinations based on the specific mechanisms of action of each drug and the anticipated synergistic effect of the combination. Androgen receptor–targeted therapy plus PARP inhibition is being examined in several ongoing phase III clinical trials, as discussed in this previous ClinicalThought™ commentary by Johann Sebastian de Bono, MB, ChB, FRCP, MSc, PhD.
Can PARP Inhibition Improve the Efficacy of Checkpoint Inhibitors in Prostate Cancer?
Rationale: Checkpoint inhibitors have limited efficacy in prostate cancer as single agents; thus, combination approaches are being examined to potentially improve their efficacy in this disease. The potential for synergy between PARP inhibitors and immune checkpoint inhibitors is based on evidence that DNA damage resulting from PARP inhibition activates the cGAS-STING pathway, which subsequently activates interferon signaling, leading in turn to increased tumor immunogenicity. There is also the potential for an additive effect in tumors with high microsatellite instability and BRCA mutations. Finally, tumors with CDK12 mutations frequently respond to PARP inhibitors, and preclinical data plus genomic data from patient tumor biopsies suggest that CDK12 inactivation results in an increased burden of neoantigens, which—theoretically—should make the tumor more immunogenic.
Evidence: Immunotherapy has demonstrated little efficacy in prostate cancer, with the exception of rare patients with tumors that have a high degree of microsatellite instability. The KEYNOTE-365 study of pembrolizumab plus olaparib in biomarker-unselected patients with metastatic castration-resistant prostate cancer (mCRPC) after prior docetaxel found that 36.6% of patients had a prostate-specific antigen decrease from baseline. The KEYLYNK-010 phase III trial is designed to further explore the combination of pembrolizumab plus olaparib in patients with mCRPC in a biomarker-unselected population after progression on androgen-deprivation therapy and abiraterone or enzalutamide. The combination of nivolumab plus rucaparib in the phase II CheckMate 9KD study in mCRPC found that the highest responses were among patients with BRCA2 mutations and that the combination was not effective in patients without homologous recombination mutations. Whether synergy between checkpoint inhibitors and PARP inhibitors is strong enough to produce a clinically relevant benefit in tumors that are not intrinsically sensitive to PARP inhibitor single agents remains to be seen.
DNA Damaging Agents and PARP Inhibitors: Too Much of a Good Thing?
Rationale: DNA is constantly damaged and repaired, but cells that fail to efficiently repair DNA damage eventually die. PARP inhibitors were developed to prevent DNA repair and thus increase DNA damage, but to date, PARP inhibitors as targeted agents are limited in their efficacy to tumors with BRCA1/2 or other DNA repair mutations. Nonselective DNA-damaging agents such as platinum-based chemotherapy have long been used in cancer therapy. Combining DNA-damaging agents with PARP inhibitors would be expected to increase the tumor’s inability to repair DNA. However, the use of nonselective agents is associated with higher toxicity, raising concern that combination approaches with these agents may be more toxic. Using more specific DNA-damaging agents such as Ra-223 or 177Lu-PSMA to direct the damage to the tumor cells may result in a more favorable toxicity profile in combination with PARP inhibitors than would be expected with nonselective DNA-damaging chemotherapies.
Evidence: Retrospective evidence suggests that DNA repair mutations sensitize prostate cancer to platinum-based chemotherapy. Limited data on DNA damaging agents with PARP inhibitors are currently available, but numerous early phase trials are ongoing. NiraRad is a phase Ib dose-finding study of niraparib with Ra-223, and 10% of patients with mCRPC and bone metastases experienced a prostate-specific antigen decrease ≥50%; all responding patients were chemotherapy naive. A phase II study of niraparib plus radiation and androgen-deprivation therapy in patients with high-risk localized prostate cancer without metastatic disease is currently enrolling (NADIR, NCT04037254). Another accruing trial is a phase I/II study of olaparib plus Ra-223 for patients with mCRPC and bone metastases (NCT03317392). The phase III VISION trial demonstrated the efficacy of 177Lu-PSMA in previously treated mCRPC, and trials examining its efficacy in other prostate cancer disease settings are ongoing. The combination of olaparib and 177Lu-PSMA is being examined in a phase I trial in mCRPC (NCT03874884).
Anti-VEGF Therapies and PARP inhibitors: Hypoxia-Induced BRCAness
Rationale: In the absence of a BRCA mutation, a similar phenotype—known as BRCAness—is present under certain conditions, one of which is hypoxia. Hypoxic conditions downregulate genes involved in homologous recombination repair in preclinical models of prostate cancer producing intratumor hypoxia and increased genomic instability.
Evidence: In ovarian cancer, there are promising results with combinations of VEGF-targeted therapies and PARP inhibitors. However, both types of agents are independently active in ovarian cancer—unlike in prostate cancer, where VEGF-targeted therapies have not demonstrated clinically meaningful activity. The antiangiogenic agent cediranib in combination with olaparib demonstrated an improvement in radiographic progression-free survival vs olaparib alone in a phase II trial of patients with mCRPC. The improvement in radiographic progression-free survival was greatest among patients whose tumors have homologous recombination deficiencies, with limited benefit of the combination in patients without such deficiencies.
The many combinations of PARP inhibitors with other agents offer additional treatment opportunities for our patients with prostate cancer, with the possibility of extending the benefit of PARP inhibition beyond those with mutations in DNA repair. However, many questions remain, including identifying the optimal target population and predictive biomarkers for each combination, as well as balancing the adverse event profile of combination therapy with its clinical benefit.
What questions do you have about PARP inhibitor combinations in prostate cancer? Do you currently consider clinical trials for your patients with prostate cancer? Answer the polling question and join the conversation by posting a comment in the discussion section.