Multiple recent US Food and Drug Administration (FDA) approvals have provided additional treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC), including ¹⁷⁷Lu-PSMA-617 and several PARP inhibitors as monotherapy and combination therapy. Neeraj Agarwal, MD, FASCO, discusses these recent FDA approvals and the data supporting the real-world clinical application of these treatments for patients with mCRPC.

The VISION trial demonstrated the superiority of ¹⁷⁷Lu-PSMA-617 in patients with mCRPC who had disease progression on at least 1 ARPI and 1 or 2 taxane-based chemotherapy regimens. It improved radiographic progression-free survival (rPFS) by approximately 5 months compared with standard of care, with an approximately 60% reduction in the risk of radiographic progression (median, 8.7 vs 3.4 months), and had an overall survival (OS) benefit of 4 months, with an approximately 40% reduction in the risk of death (median, 15.3 vs 11.3 months). These data established ¹⁷⁷Lu-PSMA-617 therapy as one of the standard-of-care options for patients with mCRPC who have progressed on an ARPI plus chemotherapy.

¹⁷⁷Lu-PSMA-617 therapy was recently granted expanded approval by the FDA for patients with mCRPC whose disease has progressed on an ARPI in whom it is considered appropriate to delay taxane-based chemotherapy or in those who have already received it, based on results from the PSMAfore trial. What sets this trial apart from others is that ¹⁷⁷Lu-PSMA-617 therapy was compared head-to-head with a change in ARPI treatment. In this trial, we saw an improvement in median rPFS (11.6 vs 5.59 months) with an approximately 50% reduction in the risk of radiographic progression or death. Most of the patients crossed over from an ARPI to ¹⁷⁷Lu-PSMA-617, so the median OS was similar in both arms, at approximately 24 months. Overall, I would say that ¹⁷⁷Lu-PSMA-617 has demonstrated clinical benefit and an acceptable side effect profile, making it an attractive treatment option for patients with mCRPC.

Interestingly, the PR.21 trial showed that chemotherapy is also a viable option in certain patient populations. In the real-world setting, often only up to 40% of patients with mCRPC are treated with chemotherapy, for many reasons. This is an older patient population, and the side effects of chemotherapy, especially febrile neutropenia, can be life-threatening for these individuals. However, this small phase 2 trial found that the median rPFS was similar for patients who received docetaxel chemotherapy or ¹⁷⁷Lu-PSMA-617 (10.7 vs 8.6 months), and the median OS numerically favored docetaxel (18.2 vs 14.3 months).

In the United States, among patients with mCRPC who receive first-line therapy, approximately 50% and approximately 75% do not receive second- or third-line therapy, respectively. So, if I see a patient who is rapidly progressing, I tend to give docetaxel to prevent a delay in the treatment because we do not need prior authorization for this. In the meantime, I order the prostate-specific membrane antigen positron emission tomography scan and get preauthorization for ¹⁷⁷Lu-PSMA-617.

More recently, we have had multiple FDA approvals for PARP inhibitors for mCRPC. In 2020, for monotherapy, rucaparib was approved for patients with BRCA mutations and olaparib approved for patients with HRR mutations. Then, in 2023, for combination therapy, we saw the FDA approvals of olaparib plus abiraterone acetate and prednisone or prednisolone, as well as niraparib plus abiraterone acetate and prednisone, for patients with BRCA mutations. Also in 2023, the combination of talazoparib plus enzalutamide was FDA approved for patients with HRR mutations.

Overall, I think that the most compelling treatment options for patients with mCRPC who have progressed on an ARPI are ¹⁷⁷Lu-PSMA-617 therapy and chemotherapy with docetaxel or cabazitaxel. Additionally, as previously noted, for patients with HRR mutations (including BRCA mutations), we have PARP inhibitor monotherapy with olaparib and enzalutamide-based ARPI combination therapy with talazoparib. For patients with BRCA mutations, we have rucaparib monotherapy and abiraterone acetate–based ARPI combination therapy with niraparib and prednisone as well as with olaparib and prednisone or prednisolone.