Lu-177-PSMA-617 vs Jevtana (cabazitaxel): which should I do next?

We saw recently (see this link) that of chemo and hormonal medicines for metastatic castration-resistant prostate cancer (mCRPC), Jevtana (cabazitaxel) is the preferred third treatment after Taxotere (docetaxel) and Zytiga (abiraterone) or Xtandi (enzalutamide). But when should radiopharmaceuticals, either approved ones like Xofigo (Ra-223), or prospective ones like Lu-177-PSMA-617, be used in the optimal sequencing?

Michael Hofman reported the results of the TheraP randomized clinical trial (RCT). They randomized some well-selected patients to receive either Lu-177-PSMA-617 or Jevtana. Patients were selected according to the following criteria;

• mCRPC (PSA≥20 ng/ml and rising)
• must have had docetaxel
• must have had either Zytiga or Xtandi or both
• healthy, with good liver, kidney, and blood function

In addition, all patients received both an FDG PET scan and a PSMA PET scan. They were excluded from the trial if either:

• Their metastases were insufficiently PSMA-avid - (10% excluded)
• There were many metastases that showed up on FDG but not on PSMA PET scans (as described here) - (18% excluded)
• 85 patients were treated with Jevtana
• 98 patients were treated with Lu-177-PSMA-617

The endpoint used was the percent of patients whose PSA declined by at least 50% (PSA50) from baseline after the treatment. After a median follow-up of 13 months:

• Lu-177-PSMA-617 had a PSA50 of 66% vs 37% for Jevtana
• The percent who had PSA progression was 31% less in those getting Lu-177-PSMA-617 relative to those getting Jevtana
• At 12 months, progression-free survival was 19% for Lu-177-PSMA-617 vs 3% for Jevtana
• Pain improvement was better for Lu-177-PSMA-617 (60%) than Jevtana (43%)
• It is too early for data on overall survival (see below for update)
• Serious/life-threatening adverse events occurred in 33% of those taking Lu-177-PSMA-617 vs. 53% of those taking Jevtana
• The most common adverse events reported by those taking Lu-177-PSMA-617 were fatigue, pain, nausea, dry mouth/eyes, low platelets, and anemia. Only 1 patient discontinued for toxicity.
• The most common adverse events reported by those taking Jevtana were fatigue, pain, diarrhea, nausea, loss of taste, neuropathy, dry mouth, and neutropenia, 3 patients discontinued for toxicity

(update 12/23) With longer term follow-up, it became apparent that although Lu-177-PSMA-617 was quicker to reduce PSA, there was no survival difference. After a follow-up of 36 months:

• Overall survival was 19.1 months for those starting with Jevtana vs 19.6 months for those starting with Lu-177-PSMA-617 (not statistically different)

This study further highlights the importance of getting both an FDG and a PSMA  PET scan at about the same time. (update 10/17/22) SUVmean>10 was a good biomarker for predicting whether Lu-177-PSMA-617 will succeed. High FDG PET predicted poor treatment response.

PSMA expression is highly variable. It is not expressed in low-grade cancer in the prostate. Expression increases as metastases develop, reach a peak, and then decreases. PSMA expression also increases when second-line hormonals are first used, but then decreases with continued use. Given this variation over time and treatment, several questions about PSMA-targeted therapy remain unanswered:

• Should it be used soon after second-line hormonals?
• Should it be used before or soon after docetaxel? (see this link)
• Would the problem of heterogeneity be minimized if Jevtana and Lu-177-PSMA were given simultaneously?
• Should it be used in minimally metastatic patients?
• Should it be used in newly diagnosed metastatic patients?
• Should it be used with immunotherapies (e.g., Provenge, Checkpoint inhibitors)?
• Will PARP inhibitors enhance the cell-kill rate?
• Is PSA the best biomarker of effectiveness?
• What are the best radionuclides to use (e.g., Ac-225, Th-227)?
• What are the best/most specific ligands to use? (e.g., PSMA-617, PSMA-I&T)
• Are there better surface proteins to target, perhaps simultaneously (e.g., FAPI)
• How do they compare to PSMA BiTE therapies?
• How does it compare to Xofigo for bone metastases?

A PSMA-based PET scan can change salvage radiation treatment decisions

The new PSMA-based PET scans provide a way to locate exactly where the cancer has spread to after an unsuccessful prostatectomy. Formerly, the only tools we had were scans that could only detect very large or rapidly growing tumors at PSAs well above the levels most radiation oncologists would be comfortable treating with salvage radiation; that is, there is widespread agreement that success rates improve the lower the PSA is when SRT is used. Even the newly approved Axumin PET scan only detects cancer in 38% of patients if their PSA is in the range of 0.2-1.0 ng/ml. By contrast, as we saw recently, the Ga-68-PSMA-11 PET scan has detected cancer in half of men when their PSA was still below 0.2, and in about two-thirds of men whose PSA was 0.2 - 0.4. The PSMA-based PET scan has the power to change SRT treatment decisions.

Calais et al. reported the results of a multi-institutional study of the Ga-68-PSMA-11 PET/CT in 270 men with biochemically recurrent prostate cancer after prostatectomy while their PSAs were still below 1.0 ng/ml (median 0.44). The institutions comprised UCLA, Technical University of Munich, Ludwig-Maximillian University of Munich, and University of Essen. Patients received PET scans from 2013-2017. Researchers painstakingly mapped all sites of cancer to find the locations of cancer that would have been missed if they had just blindly treated the prostate bed and/or the pelvic lymph node field recommended by RTOG guidelines.

The following table shows how treatment decisions might change based on their findings.

So, all in all, about half of treatment decisions might change - 30% in a minor way, 19% in a major way. The major changes would be: 

• forgoing SRT entirely in up to 12%
• consider metastasis-directed radiation in 8% - a treatment of unknown significance
• changing from prostate bed-only to whole pelvic SRT in 11%, so as to potentially render curative what would have been a non-curative treatment
• expanding the pelvic treatment field in 7%, so as to potentially render curative what would have been a non-curative treatment

At the above institutions, extended pelvic lymph node dissection (ePLND) is common practice - 81% of patients had a PLND. Consequently, 20% of patients already had detected pelvic LNs (N1) before the scan. At many institutions in the US where ePLND is less common in intermediate and high risk patients, this can cause a much larger and potentially curative change in the treatment plan from prostate bed-only to whole pelvic radiation. The researchers are to be congratulated for the painstaking work in contouring and comparing so many pelvic scans.

As one might expect, PSMA-based cancer detection was higher for those with Gleason score more than 7, and those with pathological stage N1 and T3. The patient's PSA at the time of the scan played a major role. While almost two-thirds had a PSA ≤ 0.5 ng/ml, the detection rate was 41% for those patients vs. 60% for those with higher PSAs. While detection improves with higher PSA, it is important for patients to understand that it is unwarranted (and potentially unsafe) to wait for PSA to rise just so that more cancer can be detected. That would be a self-fulfilling prophecy: by waiting for the cancer to put out more PSA, one is virtually ensuring that the cancer will grow, spread, and possible metastasize. Although we await definitive clinical trial data, most radiation oncologists recommend early treatment (before PSA reaches 0.2 ng/ml) for men with adverse pathology or for those evincing a distinct pattern of PSA progression after prostatectomy.

While a previous analysis showed that the Ga-68-PSMA PET had little effect on SRT decisions, and no patients were upgraded from incurable to potentially curable, this larger, more detailed study indicates that about 1 in 5 patients can be upgraded, and 1 in 6 can be spared SRT. This would seem to justify the cost. UCLA charges $2650 for recurrent (and high risk) patients. NIH is recruiting recurrent and high risk patients for an improved PSMA-based PET scan (called DCFPyL) that  is free (and transportation to Washington D.C. is covered as well).

PSMA PET finds more cancer than Axumin

A PSMA PET scan (Ga-68-PSMA-11) detected more sites of cancer than an Axumin PET scan in the same recurrent patients. This prospective clinical trial was  conducted among 50 men at UCLA in 2018. All men had post-prostatectomy PSA from 0.2- 2.0 ng/ml.  The Calais et al. findings are summarized in the following table:

	Ga-68-PSMA-11	Axumin
Detected - % of patients	56%	26%
Prostate bed	14%	18%
Pelvic lymph nodes	38%	8%
Extra-pelvic lesions	16%	0%

The two scans performed equally well at detecting recurrence in the prostate bed, but the PSMA PET scan was able to detect more cancerous pelvic lymph nodes and non-regional metastases. The surprising result is that more recurrences are attributable to pelvic lymph nodes (stage N1) or to extra-pelvic metastases (stage M) than to cancer in the prostate bed. If this is true of all recurrent men, it indicates that salvage whole pelvic radiation is usually preferred over salvage prostate bed radiation. We saw (see this link) that salvage whole pelvic radiation improved progression-free survival compared to salvage prostate bed-only radiation. But in that SPPORT trial, the authors noted that the improvement did not hold up at low PSAs. Even the best PSMA PET/MRI has a tumor size detection limit of about 4 mm. If cancer in the pelvic lymph nodes is still curable, it may be necessary to treat cancer while it is still undetectable.

The detection rate by PSA was as follows, but is based on small numbers of patients in each PSA group. The differences in the detection rates are statistically significant for PSAs over 0.5:

PSA (ng/ml)	Ga-68-PSMA-11	Axumin
0.2-0.5 (n=26)	46%	27%
0.51-1.00 (n=18)	67%	28%
1.01-2.00 (n=6)	67%	17%

The other PSMA-based PET scan, DCFPyL, has completed recruiting.

(update 12/19/20) In a meta-analysis - in different patients - the detection rates were as follows:

PSA (ng/ml)	Ga-68-PSMA-11 n = 3,217 in 38 studies	Axumin n = 482 in 6 studies
0.2-0.5	45%	37%
0.51-1.00	59%	48%
1.01-2.00	80%	62%

The difference for PSAs from 1-2 ng/ml is statistically significant.

FDA has approved the Ga-68-PSMA PET/CT at UCLA and UCSF.