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Impact of TP53 Loss-of-Function Alterations on the Response to PSMA Radioligand Therapy in Metastatic Castration-Resistant Prostate Cancer Patients - Beyond the Abstract

Prostate-specific membrane antigen (PSMA)-radioligand therapy (PSMA-RLT) with the radioisotope lutetium-177 (177Lu) has emerged as a promising treatment for metastatic castration-resistant prostate cancer (mCRPC). The phase 3 VISION trial demonstrated that 177Lu-PSMA-617 significantly improved progression-free survival (PFS) by over five months and overall survival (OS) by four months in mCRPC patients who had previously received androgen receptor signaling inhibitors (ARSI) and taxanes. This led to FDA approval in March 2022 and EMA approval in December 2022. The more recent phase 3 PSMAfore trial further demonstrated a six-month PFS benefit of 177Lu-PSMA over an ARSI switch in taxane-naïve mCRPC patients, though no OS difference was observed.

A key challenge with PSMA-RLT, as with any new therapy, lies in identifying reliable biomarkers to guide patient selection and optimise treatment outcomes. PSMA-RLT induces a broad range of DNA damage, including single- and double-strand DNA breaks (SSBs and DSBs). Based on this mechanism, we initially hypothesized that patients with deficiencies in homologous recombination repair, like those with BRCA mutations, might exhibit enhanced responses. However, studies -including our own- have not established a strong association between HRR deficiency and PSMA-RLT efficacy. This lack of association may stem from the diverse types of DNA damage induced by ionizing radiation from PSMA-RLT, which is not limited to DSBs.

TP53 is a key regulator in the DNA damage response to both SSBs and DSBs. Loss-of-function alterations in TP53 have been identified as a prognostic biomarker indicating poor response to PSMA-RLT in our study. Patients with TP53 loss-of-function alterations had significantly worse outcomes, such as a shorter PFS of 3.7 months compared to 6.2 months, a less pronounced median PSA reduction (-55% versus -75%), and a shorter OS from the start of PSMA-RLT (7.6 months versus 13.9 months). None of the other genetic subgroups were associated with response to PSMA-RLT. Previous studies have not consistently demonstrated a link between TP53 loss-of-function and PSMA-RLT response but all were retrospective of nature and smaller in sample size.

This year, in line with our findings, Dr. Johann de Bono presented an exploratory analysis between baseline circulating tumour DNA and outcomes on 177Lu-PSMA-617 from the phase 3 PSMAfore trial. This analysis showed that patients with deleterious alterations in TP53 had shorter radiographic PFS (6.1 versus 9.2 months, p<0.01) than patients with wildtype TP53, further supporting the notion that TP53 alterations are prognostic biomarkers of poorer outcomes with 177Lu-PSMA.

In our study, we also explored whether TP53 might have predictive value beyond its prognostic role. There are multiple hints from preclinical studies that TP53 loss-of-function might be predictive of poor response to 177Lu-PSMA. However, our data showed a comparable OS deficit in TP53-mutated patients regardless of whether they received PSMA-RLT, indicating that TP53 status might be only prognostic rather than also predictive for PSMA-RLT response. This finding was again reinforced by the PSMAfore trial, where TP53-mutated patients treated with 177Lu-PSMA-617 had a longer PFS than those treated with a change in ARSI (6.1 versus 2.4 months), despite having a poorer PFS on 177Lu-PSMA-617 than TP53 wildtype patients.

Although TP53 loss-of-function alterations are a prognostic marker for poor outcomes with 177Lu-PSMA, patients with such alterations should not be excluded from this therapy, as they tend to fare even worse with ARSI treatments. Notably, studies by De Laere et al. (2024) and Graf et al. (2022) have shown that the prognostic impact of TP53 mutations is less pronounced with taxanes compared to ARSI. This raises a critical clinical question: should taxanes be preferred over 177Lu-PSMA in mCRPC patients with TP53 loss-of-function alterations? Unfortunately, major trials like VISION, LuPSMA, and PSMAfore did not directly compare 177Lu-PSMA with taxane-based chemotherapy. The TheraP trial, which compared 177Lu-PSMA-617 to cabazitaxel, showed higher PSA response rates with 177Lu-PSMA-617, but updated results revealed no significant difference in overall survival (OS) between the two treatments. Unfortunately, genetic biomarkers, including TP53 status, were not evaluated, leaving the question of whether patients with TP53 loss-of-function might benefit more from taxanes or PSMA-RLT unanswered.

Conclusion
TP53 loss-of-function alterations are prognostic for poorer outcomes in mCRPC patients treated with 177Lu-PSMA, with available data still supporting the efficacy of 177Lu-PSMA over an ARSI. Whether taxanes might be a better option for these patients remains to be elucidated, and prospective biomarker-guided studies are needed to directly compare the efficacy of 177Lu-PSMA and taxanes for patients with TP53 loss-of-function alterations.

Written by: Peter H. J. Slootbeek,1 María Victoria Luna-Velez,2 Bastiaan M. Privé,3 Maarten J. van der Doelen,2 Iris S. H. Kloots,1 Samhita Pamidimarri Naga,1 Hilde E. Onstenk,1 James Nagarajah,3,4 Harm Westdorp,1 Inge M. van Oort,2 Leonie I. Kroeze,5 Jack A. Schalken,2 Haiko J. Bloemendal,1 Niven Mehra1

  1. Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.
  2. Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands.
  3. Department of Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
  4. Roentgeninstitut Duesseldorf, Duesseldorf, Germany.
  5. Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands.
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