Pluvicto May Slow Progression Earlier in Advanced Prostate Cancer

Patients with advanced prostate cancer who received Pluvicto had promising progression outcomes.

Among patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) who experienced disease progression following prior treatment with an androgen receptor pathway inhibitor (ARPI), treatment with the radioligand therapy Pluvicto (lutetium Lu 177 vipivotide tetraxetan, also known as 177Lu-PSMA-617), resulted in favorable outcomes regarding progression and response compared to patients treated with another ARPI, researchers have reported.

A follow-up analysis of results from the phase 3 PSMAfore study, findings of which were presented at the American Urological Association Annual Meeting and published in The Journal of Urology, showed that Pluvicto prolonged radiographic progression-free survival (rPFS; no signs of disease progression on professional imaging) and increased PSA50 responses (a decline of at least 50% from baseline in prostate-specific antigen, a protein associated with the presence of prostate cancer in the body) and objective response rate (ORR; patients who responded completely or partially to treatment).

The trial included 468 patients with PSMA-positive mCRPR who had progressed after previous ARPI treatment and had not been treated with chemotherapy for metastatic disease.

Patients treated with abiraterone and then Pluvicto experienced a median rPFS of 12.62 months, versus 5.78 months for those treated with abiraterone and then another ARPI. Likewise, patients treated with Xtandi (enzalutamide) and then Pluvicto saw a median rPFS of 12.02 months, compared to 4.34 months for those treated with Xtandi and another ARPI.

Similar dynamics were echoed with regard to PSA50 rates, which were 64.2% for patients receiving abiraterone then Pluvicto and 25.6% for those switching from abiraterone to another ARPI. The rates were 51.7% for those treated with Xtandi then Pluvicto, and 12.5% for those treated with Xtandi then another ARPI. Objective response rates for the four patient cohorts were 61.1%, 16.2%, 40% and 13.3%, respectively.

Pluvicto was approved by the Food and Drug Administration in 2022 to treat patients with PSMA-positive mCRPC, including those previously treated with other therapies including ARPIs and taxane-based chemotherapy. The current study findings show the drug’s efficacy prior to chemotherapy, and regardless of which ARPI they’d previously received, according to study co-author Dr. Xiao X. Wei, a medical oncologist at the Dana-Farber Cancer Institute in Boston.

“Our question was, basically, do we see a benefit independent of what patients had received prior to randomization, which dictated what they received on treatment if they're randomized to the ARPI change? And what we found was that, indeed, regardless of whether a patient had received prior abiraterone or [Xtandi], we saw a meaningful improvement in rPFS as well as PSA50 response and objective response rates in these two subgroups,” Wei told CURE®.

In a previous interview with CURE®, Wei’s co-author Dr. Neal Shore, steering committee chair and medical director, Carolina Urologic Research Center, explained the mechanism by which androgen receptor pathway inhibitors work.

“All cells have lots of receptors that stick off the outer area of the cell, the cell membrane. And the key prostate cancer receptor is called the androgen receptor, it's sort of flopping in the breeze out there in the bloodstream,” Shore said. “And it can get turned on by different fuel sources and the chief fuel source is testosterone, there are metabolites of testosterone, but the key ones we call testosterone and dihydrotestosterone. But that acts as a fuel that when that metabolite — that hormone, testosterone — comes into contact with the receptor, it turns it on, goes back into the cell and the cells start to proliferate and you make more.

“The analogy that I use is the testosterone is the fuel. So, if you want to stop the car from moving, you take your foot off the gas pedal. But if you further want to stop the car from moving, not only do you take your foot off the gas pedal, you put your foot also on the brake — foot on the brake, foot off the gas. The … androgen receptor pathway inhibitor is putting your foot on the brake of the androgen receptor.”

In turn, Wei described the function of a radioligand therapy such as Pluvicto.

“Radioligand therapy in general is a relatively newer, innovative approach that we use to treat certain types of cancer including prostate cancer,” Wei said. “How it works is that it delivers radiation systemically and specifically targeting cancer cells. So, the target of Pluvicto works on this PSMA or prostate-specific membrane antigen. And PSMA is overexpressed in prostate cancer cells, particularly in prostate cancer that's metastatic and hormone-resistant [when a patient’s cancer progresses despite a low testosterone state].

“So, the treatment is delivered intravenously and then travels throughout the body and it selectively homes in to cancer cells that express PSMA through a process called endocytosis, where the treatment's actually delivered into the cells and the payload, the radiation, in this case beta radiation, is emitted and leads to DNA damage, leading to cell death and by way of targeting PSMA-expressing cells it minimize this effect to healthy cells that don't express PSMA.”

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