AUA 2019: RESIST-PC Phase 2 trial: 177Lu-PSMA-617 Radionuclide Therapy for mCRPC - Jeremie Calais

Chicago, IL ( PSMA/PET scans have been gaining increasing popularity in the field of prostate cancer diagnostics. Due to its high specificity for prostate cancer, especially in contrast to benign prostate tissue, it potentially has a role in multiple stages of prostate cancer diagnostics, including in the biochemical recurrence setting and pre-operative staging. Considering the relatively low sensitivity and specificity of standard staging studies, particularly at lower PSA levels, there is great excitement about the potential impact of PSMA/PET scans and other so-called “functional” imaging tools.

One potential advantage of these functional imaging tools, due to their specificity for prostate cancer over benign prostate tissue, is their role in theranostics (therapeutic diagnostics). By linking therapeutic agents to the radioligand, direct delivery of the therapeutic agent to the cancer may be achieved – potentially with less systemic adverse events. 177Lu-PSMA-617 Radionuclide Therapy is one such option, with prior studies reporting significant responses in a subset of patients.

This particular abstract is an investigator-initiated open-label prospective bi-centric single-arm phase 2 clinical trial of 177Lu-PSMA-617 radionuclide therapy in patients with progressive metastatic castrate-resistant prostate cancer (mCRPC). These patients have often exhausted many of the first and second line therapies. As such, additional systemic therapy may not have much efficacy – but will come with potentially significant side effects.

Specifically, they included patients with progressive mCRPC (defined as either biochemical, radiographic or clinical progression) after at least 1 novel androgen axis drug (NAAD), such as enzalutamide, abiraterone or apalutamide. These patients may have been either chemotherapy (CTX) naive or post-CTX (typically docetaxel). They must also have sufficient bone marrow reserve and normal kidney function to be eligible (as the agents are cleared renally). 

Jeremie Calais notes that this study was patient-funded and patients paid for the study themselves – and it cost about $10,000 per cycle – and the goal was to get 4 cycles, but the efficacy was assessed after each cycle. 

All patients underwent a screening PSMA PET/CT to confirm target expression – if they are PSMA negative (~10% of advanced prostate cancers are PSMA negative), then there is no utility to giving the tagged agent. Patients then received up to 4 cycles of 177Lu-PSMA-617 every 8 weeks, give or take 1 week, and were randomized into 2 treatment activities groups based on dosage (6.0 or 7.4 GBq). Kidney dosimetry was performed for the first cycle. 

Primary outcome was efficacy, which was defined as serum PSA decline of >=50% from baseline at 12 weeks. Safety was also a primary outcome.

64 patients were included in the study. In July 2018, the company stopped the trial – so no further enrollment was allowed. This fell well below the sample size of 200 that the investigators were hoping for. Full demographics are below:

  • Median PSA at the time of treatment was 75 ng/ml, the range was 0.5-2425
  • 20% were CTX naive while 80% were post-CTX (1.9 CTX regimens on average, range 1-4)
  • Androgen deprivation therapy was given concomitantly in 83%, NAAD in 23% and immunotherapy in 6%
  • Patients were randomized to either 7.4 GBq or 6 GBq – 64% in the first arm, 36% in the second group
Of the 64 patients, only 45% completed 4 cycles of 177Lu-PSMA-617. The remaining had 1-3 cycles. Tolerability: Mild and transient (CTCAE grade 1-2) side effects included xerostomia (72%), nausea/vomiting (69%) and bowel movement disorders (45%). CTCAE grade 3 toxicity included nausea/vomiting (6%), anemia (8%), leukopenia (5%), kidney failure (3%), thrombocytopenia (3%), and neutropenia (3%). 

In terms of response, the PSA decline of >=50% was observed in 23% of patients at 12 weeks and in 38% of patients at any time (best PSA response). 16% had a PSA decline of >=90% while 59% had any PSA decline (>0%). 

The response rate by number of cycles in seen below:

By 12 weeks, they had generally received only 2 cycles. Interestingly, on an analysis of best response, it appeared that the best response happened after the 3rd cycle - the median time to best PSA response was 22 weeks (range 6-49 weeks). So perhaps the investigators were too premature with their time cutoff.  However, he did note that 11 patients are still on active surveillance and have had good response.

The mean kidney dose was 2.7 Gy for the first cycle (range 0.9-5.9) i.e. 0.4 Gy/GBq (range 0.15-0.9). There was no difference between the efficacy and toxicity for the 6.0 GBq (n=23) and 7.4 GBq (n=41) treatment arms.

In terms of secondary outcomes, there was no difference in PFS – seen below:

Considering that many of these patients had already failed first and second line therapies, these responses are encouraging. 177Lu-PSMA-617 radionuclide therapy appears to be well tolerated in patients with progressive mCRPC. PSA declined by >=50% in 38% of patients, and the best PSA response rate occurred after 3 cycles. 

Unfortunately, the trial has closed and will not meet its 200 patient expected accrual. 

Presented by: Jeremie Calais, MD, MSc, UCLA

CO-AUTHORS: Wolfgang Fendler, Matthias Eiber, Michael Lassmann, Magnus Dahlbom, Rouzbeh Esfandiari, Jeannine Gartmann, Kathleen Nguyen, Pan Thin, Ken Herrmann, Johannes Czernin, Ebrahim Delpassand

SUBMITTED BY: Thenappan Chandrasekar, MD (Clinical Instructor, Thomas Jefferson University) (twitter: @tchandra_uromd, @JEFFUrology) at American Urological Association's 2019 Annual Meeting (AUA 2019), May 3 – 6, 2019 in Chicago, Illinois

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