PSMA RLT and Combination Therapy
Prostate cancer remains a significant healthcare challenge worldwide, necessitating the development of innovative treatment approaches. Theranostics, the integration of diagnostics and therapeutics, offers promising avenues for personalized prostate cancer management. This essay explores the potential of PSMA (Prostate-Specific Membrane Antigen) radioligand therapy (RLT) and its combination with PARP inhibitors and other treatments as a future direction in prostate cancer therapeutics.
Prostate cancer is one of the most prevalent malignancies among men, with varying clinical courses and outcomes. Despite significant advancements in conventional treatments, the heterogeneity of the disease calls for targeted and personalized approaches. Theranostics, a rapidly evolving field, holds immense potential to revolutionize prostate cancer management by combining diagnostics and therapeutics, tailoring interventions to the individual patient’s biology. PSMA, a cell surface marker highly expressed in prostate cancer cells, has emerged as a prime target for theranostic interventions, including radioligand therapy (RLT) and combination therapies.
PSMA Radioligand Therapy (RLT): PSMA RLT involves the administration of a radioactive ligand that selectively binds to PSMA-expressing prostate cancer cells, delivering a therapeutic dose of radiation directly to the tumor. This targeted approach allows for precise treatment of cancerous cells while sparing healthy surrounding tissues, reducing the risk of adverse effects associated with conventional radiotherapy. Clinical trials have shown promising results, demonstrating improved tumor response rates and prolonged survival in patients with metastatic castration-resistant prostate cancer (mCRPC). The future of PSMA RLT lies in optimizing radioligands, enhancing patient selection criteria, and exploring combination therapies and isotopes to maximize treatment efficacy.
Combination Therapy with PARP Inhibitors: Poly (ADP-ribose) polymerase (PARP) inhibitors have shown significant clinical success in treating various cancers, particularly those with defects in homologous recombination DNA repair, such as BRCA1/2 mutations. The concept of combining PARP inhibitors with PSMA RLT in prostate cancer holds great promise. PARP inhibitors can sensitize cancer cells to radiation by inhibiting DNA repair mechanisms, making them more susceptible to the radiation damage induced by PSMA RLT. Moreover, this combination may overcome resistance mechanisms that can arise with monotherapy. Ongoing trials exploring this combination have shown encouraging results, emphasizing the potential of personalized therapeutic strategies for prostate cancer patients.
Early findings from the phase 1 LuPARP study (NCT03874884) demonstrated that patients with metastatic castration-resistant prostate cancer (mCRPC) experienced enhanced antitumor activity following treatment with the PARP inhibitor olaparib (Lynparza) in addition to the radioligand lutetium Lu 177 vipivotide tetraxetan (Pluvicto; formerly 177Lu-PSMA-617) .
Combination Therapy with Other treatments: In addition to PARP inhibitors, combining PSMA RLT with other isotopes (alpha emitters, Auger electrons) or agents (FAPi, DLL3) offers a multifaceted approach to tackle prostate cancer. Traditional chemotherapies, such as taxanes and platinum-based drugs, have demonstrated efficacy in prostate cancer treatment. Their combination with PSMA RLT could potentially enhance treatment outcomes through synergistic effects, leading to improved disease control and survival rates. Clinical trials evaluating these combinations are essential to validate their safety and efficacy and guide the development of evidence-based treatment guidelines [2, 3].
The future of theranostics in prostate cancer management is promising, with PSMA RLT serving as a pivotal component of personalized treatment strategies. The integration of PSMA RLT with PARP inhibitors and other treatments represents a paradigm shift in prostate cancer therapeutics, offering the potential for improved outcomes and reduced side effects. As ongoing research continues to uncover novel insights into the biology of prostate cancer, it is imperative to remain vigilant in evaluating the safety and efficacy of these combination therapies through well-designed clinical trials. By embracing theranostics and harnessing the power of personalized medicine, we can aspire to transform the landscape of prostate cancer care and ultimately improve patient outcomes and quality of life [2, 3].
- Sandhu S, Joshua AM, Emmet L, et al. LuPARP: phase 1 trial of 177Lu-PSMA-617 and olaparib in patients with metastatic castration resistant prostate cancer (mCRPC). J Clin Oncol. 2023;41(suppl 16):5005.
- doi:10.1200/JCO.2023.41.16_suppl.5005https://doi.org/10.36255/exonpublications. prostate cancer theranostics. 2021
- Shahneen Sandhu, Christina Guo and Michael S. Hofman. Radionuclide Therapy in Prostate Cancer: From Standalone to Combination PSMA Theranostics. Journal of Nuclear Medicine December 2021, 62 (12) 1660-1668; DOI: https://doi.org/10.2967/jnumed.120.243295