The results of the UpFrontPSMA trial are in, unveiled during the ESMO 2024 in Barcelona, and they are truly encouraging for the future of prostate cancer treatment. ¹⁷⁷Lu-PSMA radioligand therapy (RLT) has taken a significant leap forward in the treatment protocol, now positioning ahead of docetaxel chemotherapy. Initially introduced after the VISION trial as a last-in-line therapy for advanced metastatic castration-resistant prostate cancer in heavily pre-treated patients, this RLT has shown remarkable efficacy and a favorable safety profile, allowing it to move closer to the forefront of treatment options. In fact, it seems like the earlier, the more effective it is.

Trial Overview

The UpFrontPSMA phase 2 trial evaluated the efficacy of administering ¹⁷⁷Lu-PSMA prior to docetaxel compared to docetaxel alone in patients newly diagnosed with high-volume metastatic hormone-sensitive prostate cancer (mHSPC). The experimental group received two cycles of ¹⁷⁷Lu-PSMA (7.5 GBq each) followed by six cycles of docetaxel, while the control group received only docetaxel. The primary endpoint^[1] was achieving undetectable prostate-specific antigen (PSA) levels after 48 weeks—a high bar for success.

Participant Selection Criteria

The most critical selection criterion for the trial was high PSMA uptake, with patients requiring a SUVmax above 20 based on ⁶⁸Ga-PSMA PET/CT scans. (As researchers reported, some patients had to be excluded despite having initially demonstrated PSMA-avid lesions. This exclusion occurred because androgen deprivation therapy (ADT) prior to treatment led to downregulation of PSMA expression.)

Adverse Events

The combination of ¹⁷⁷Lu-PSMA with docetaxel did not result in increased toxicity. The most common severe adverse events were the same in the two groups:

• febrile neutropenia (11% in the combination experimental group vs. 10% in the docetaxel-alone control group) and
• diarrhoea (6% in the combination group vs. none in the control group).

The only adverse event that was different in the experimental arm was dry mouth, a known common side effect of the ¹⁷⁷Lu-PSMA. But even this one was all grade 1, so very mild.

Being a targeted therapy, ¹⁷⁷Lu-PSMA was well tolerated with fewer side effects, resulting in better quality of life (QoL). Unlike docetaxel, which caused a rapid decline in QoL, patients receiving ¹⁷⁷Lu-PSMA maintained their well-being longer, with QoL dipping only after the introduction of docetaxel.

Protocol Considerations

There were some concerns about whether the experimental arm might have been underdosed, as only two cycles of ¹⁷⁷Lu-PSMA were administered. Typically, three cycles are standard practice. However, the trial's design aimed to avoid delaying conventional docetaxel treatment.

As a side note, our clinic follows a stricter protocol, spacing the cycles four weeks apart and not the usual six to eight based on the research of Prof. Dr. Hartenbach, our leading specialist. In general, German university hospitals, having played a pivotal role in developing PSMA-targeted therapies in the early 2000s, have accumulated significant expertise in this area.

Results

The results of the trial were highly promising. 41% of patients in the ¹⁷⁷Lu-PSMA plus docetaxel group achieved undetectable PSA levels at the 48-week mark, compared to just 16% in the docetaxel-alone group. This significant difference demonstrates the superior antitumor activity of administering ¹⁷⁷Lu-PSMA therapy before docetaxel, without an increase in toxicity. These findings promise to trigger a change in the standard-of-care and introduce ¹⁷⁷Lu-PSMA in the treatment of mHSPC at the very early stage.

^[1] The predefined, primary goal of a clinical study, against which its success is measured