Novel Radionuclide Treatment Shows Promise in mCRPC

Radionuclide treatment with Lutetium-177 [177Lu]-PSMA-617 nearly doubled median PSA progression-free survival in men with progressive metastatic castrate-resistant prostate cancer compared with previous results with radium-223.

Michael S. Hofman, MBBS

Radionuclide treatment with Lutetium-177 [177Lu]-PSMA-617 nearly doubled median PSA progression-free survival (PFS) in men with progressive metastatic castrate-resistant prostate cancer (mCRPC) compared with previous results with another radiopharmaceutical, radium-223 (Ra-223; Xofigo), according to updated results from the phase II LuPSMA study published in The Lancet Oncology.1

In LuPSMA, the median PSA PFS was 7.6 months (95% CI, 6.3-9.0) and 27 (90%) of 30 men experienced PSA progression. The median overall survival (OS) was 13.5 months (95% CI, 10.4-22.7) and 22 (73%) men had died by the November 2017 data cutoff.

“The PSA progression-free survival of 7 months noted in this study is similar to that noted in the cabazitaxel TROPIC trial and longer than the 3.6 months recorded with Ra-223,” lead author Michael S. Hofman, MBBS, the Peter MacCallum Cancer Centre, Melbourne, Australia, and colleagues wrote.

“Our results must be interpreted in the context of a heavily pretreated patient cohort who had exhausted most standard therapies, including cabazitaxel in almost 50%, and had a declining performance status,” Hofman et al added. “Indeed, any sustained response to further treatment in this setting is promising, especially if the treatment improves quality of life without significant toxic effects.”

Hofman first presented preliminary results from the LuPSMA study at the 2017 ESMO Congress. These findings published in The Lancet Oncology included updated OS and PSA PFS data.

Nearly all patients (97%) saw their PSA level decline and 57% (95% CI, 37-75) of men experienced a ≥50% reduction in PSA score, meeting the primary endpoint. Six (20%) patients had a ≥96% PSA decline.

“The greater than 50% PSA response of 57% in this study is encouraging, particularly when compared with established agents (eg, a response of 39% was observed after treatment with cabazitaxel),” investigators wrote. “Seventy-six percent of patients had a PSA response greater than 30% compared to 16% in the Ra-223 ALSYMPCA study, highlighting the advantage of a tumor-targeted compound compared with an exclusively bone-seeking agent.”

In posthoc analysis, investigators determined that a ≥50% reduction in PSA score was associated with even greater improvements in survival. The median PSA PFS was 9.9 months for patients with a ≥50% reduction in PSA score and the median OS was 17.0 months. In comparison, patients who did not have a PSA decline of ≥50% had a median PSA PFS of 4.1 months and a median OS of 9.9 months.

“This more detailed publication was consistent with or improved from the summary results presented at ESMO last fall,” Mike Sherman, president and CEO of Endocyte, said in a statement. Endocyte is developing [177Lu]-PSMA-617. “The response rates demonstrated to date are encouraging, especially since no agent has been proven to improve survival in this heavily pretreated patient population.”

Investigators at the Peter MacCallum Cancer Centre recruited 30 men into the single-arm, single-center, phase II study. All men in the study were diagnosed with mCRPC that progressed following standard treatments, including taxane-based chemotherapy and second-generation antiandrogens.

Twenty-six (87%) men had received at least 1 previous line of chemotherapy; 80% received docetaxel and 47% received cabazitaxel (Jevtana). Twenty-five (83%) had received enzalutamide (Xtandi), abiraterone acetate (Zytiga), or both.

Men in the study received a mean radioactivity of 7.5 GBq per cycle (range, 4.4-8.7) for up to 4 cycles of [177Lu]-PSMA-617 treatment administered in 6-week intervals.

Twenty-seven men (90%) reported some degree of pain at baseline, and these patients reported improvements in both severity and interference at all time point with [177Lu]-PSMA-617 treatment. By the second treatment cycle, 11 of these patients reported a ≥10-point improvement in global health score, and 10 reported a ≥1-point improvement in pain score. Investigators found that cognitive functioning, insomnia, and pain scores all improved from baseline.

[177Lu]-PSMA-617 was generally well tolerated. The most common treatment-related adverse event (TRAE) was grade 1 dry mouth (87%) that usually resolved without intervention. Of grade 3 TRAEs, 11 (37%) patients experienced lymphocytopenia, 4 (13%) experienced anemia, 3 (10%) had thrombocytopenia, 2 (7%) had neutropenia, and 1 (3%) reported pain. One patient experienced grade 4 thrombocytopenia attributed to [177Lu]-PSMA-617, the only grade 4 AE recorded in the study.

Hofman is slated to present data from this study that includes findings from an additional 20 patients at the 2018 ASCO Annual Meeting. Endocyte is scheduled to start a phase III trial of [177Lu]-PSMA-617 later this year.

The alpha-particle emitting radiopharmaceutical radium-223 was approved by the FDA in May 2013 for the treatment of patients with CRPC, symptomatic bone metastases, and no known visceral metastatic disease.

The approval was based on the phase III ALSYMPCA trial, in which radium-223 demonstrated a median OS of 14.9 months compared with 11.3 months with placebo for patients with bone-metastatic CRPC (HR, 0.70; P <.001).2 The PSA PFS was 3.6 months versus 3.4 months, respectively (HR, 0.64; 95% CI, 0.54-0.77).


  1. Hofman MS, Violet J, Hicks RJ, et al. [177Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial): a single-centre, single-arm, phase 2 study [published online May 8, 2018]. Lancet Oncol. S1470-2045(18)30198-0.
  2. Sartor O, Coleman RE, Nilsson S, et al. 3-year follow-up of chemotherapy following radium-223 dichloride (Ra-223) in castration-resistant prostate cancer (CRPC) patients (Pts) with symptomatic bone metastases (Mets) from ALSYMPCA. Presented at: 2015 European Cancer Congress; September 25-29; Vienna, Austria. Abstract 2510.
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