Pluvicto+Xtandi Delays Progression Better than Xtandi-alone in mCRPC

Both Pluvicto (177LuPSMA-617) and Xtandi (enzalutamide) have been separately shown to delay progression and extend survival among metastatic and castration-resistant men with prostate cancer (mCRPC). Because they inhibit prostate cancer in different ways, it was hoped that combining them would have an additive benefit. In a clinical trial, enzalutamide temporarily increased expression of PSMA, so a synergistic effect is possible.

Emmett et al. reported the first results of the ENZA-p trial. 162 mCRPC patients with 2 or more risk factors were treated at 15 hospitals in Australia. Unlike the VISION trial, they did not previously receive docetaxel or 2nd line hormonal treatment for mCRPC. The risk factors were:

1. metastatic at original diagnosis
2. elevated LDH, ALP, albumin (PSA> 5 ng/ml)
3. PSADT< 84 days
4. < 3 years since diagnosis
5. ≥5 bone or visceral metastases 
6. pain requiring opiates
7. received abiraterone for mHSPC (docetaxel for mHSPC was allowed)

After 20 months of follow-up, the outcomes were:

• Median PSA Progression-Free Survival was 13.0 months for the combo vs 7.8 months for enza-only
• Median Radiographic Progression-Free Survival was 16 months for the combo vs 12 months for enza-only
• Percent with >50% PSA reduction was 93% for the combo vs 68% for enza-only
• Percent with >90% PSA reduction was 78% for the combo vs 37% for enza-only
• Too early for overall survival
• Improvement in pain scores were 61% for the combo vs 27% for enza-only
• Side effects for the combo vs enza-only were fatigue (75% vs 70%), nausea (47% vs 27%), and dry mouth (40% vs 10%).
• 81% received all 4 doses of Pluvicto.

Based on these results, and pending later follow-up on overall survival, Pluvicto should be combined with enza.

The importance of Peer-Review

When I was new to prostate cancer research in 2011, I attended my first PCRI Conference. One of the presenters was Eugene Kwon. He presented some early data on an experimental new tyrosine kinase inhibitor called cabozantinib. Tyrosine kinase is an enzyme that stimulates metastatic growth. Kwon showed the following "gee whiz" images that had the whole room abuzz. It seems to show the complete resolution of numerous bone metastases on a bone scan in 3 patients in 6 or 12 weeks:

Kwon presented "Cabo" as a game-changer in PCa treatment to an auditorium full of patients and on YouTube. Was it too good to be true?

Several Phase 3 trials found that Cabo only disguised bone metastases so that they no longer showed up on a bone scan. Smith et al. (in the COMET-1 trial) showed that Cabo did not improve PSA or survival, and it had unacceptable toxicity. Basch et al. (in the COMET-2 trial) found that pain palliation was no better than mitoxantrone (an early kind of chemo.)

In spite of these negative findings, research went ahead into using Cabo with a variety of combinations. Neeraj Agarwal presented the results of the combination of Cabo+atelolizumab in the CONTACT 2 trial at an ASCO presentation. In theory, cabo makes bone metastases more permeable to immunotherapies like atelolizumab (A). And in an early Phase 1 trial it seemed to help progressed patients. 507 patients with soft-tissue mets were randomized to receive either Cabo+A or the control drug Xtandi/Zytiga (whichever one they hadn't had already). After 12 months, the results were as follows:

• Radiographic progression-free survival (rPFS) was 6.3 months for Cabo+A vs 4.2 months for the control (statistically significant)
• rPFS among men with liver metastases was 6.0 months for Cabo+A vs 2.0 months for the control (statistically significant)
• rPFS among men who had had docetaxel while hormone sensitive was 8.8 months for Cabo+A vs 4.1 months for the control (statistically significant)
• rPFS among men who had bone metastases  was 6.3 months for Cabo+A vs 4.1 months for the control (statistically significant)
• Objective Response Rate was 13.6% for Cabo+A vs 4.2% for the control (statistically significant)
• Overall survival was 16.7 months for Cabo+A vs 14.6 months for the control (not statistically significant, but data immature)
• Treatment-related adverse events (serious or life-threatening) were 33% for Cabo+A vs 8% for the control.

Agarwal concluded that Cabo+A showed a clinically meaningful improvement in PFS vs second advanced hormonal therapy. This supports Cabo+A as a potential new treatment option for mCRPC patients who have progressed on one second-line hormonal therapy.

But...

Kim Chi provided the peer review. He pointed out that:

• The differences in PFS are modest and not clinically meaningful.
• There was no difference in time to pain progression and the same deterioration in QOL.
• As in the trials of Cabo alone, there is so far no difference in survival. In the COMET 1 trial (above) there was never any difference in survival. Cabo masked the deterioration, such that it only appeared that there was an improvement in rPFS.
• The difference in rPFS is the same as with Cabo alone (about 6 months). The immunotherapy didn't seem to improve outcomes.
• The control group (switch to the untried second-line hormonal) is not what most patients would try next. They would try docetaxel (rPFS= 8-9 months), cabazitaxel (rPFS= 8 months), or Pluvicto (rPFS= 8.7 months). All provide better rPFS than Cabo+A.
• Due to toxicity, there were dose delays/holds/reductions in 40-60% of patients
• Patients would experience less toxicity and greater benefit with taxane chemotherapy.
• Low rate of subsequent therapy (25%), suggests that these patients lost an opportunity to get another life-prolonging therapy.

Patients are sometimes tempted to learn about therapies from YouTube videos and other social media. Patients should be alerted that without good peer-review they may be dangerously misled. 

Higher dose improves results in high-risk patients

GETUG-AFU-18 is another trial where the findings are obvious, and irrelevant, because radiation and hormone medication technology have improved far beyond what was available when this trial began 15 years ago, and long follow-ups are necessary to detect outcome differences in men with localized prostate cancer. A similar trial (RTOG 0126) in intermediate-risk patients found a curative benefit for the higher dose, although no increase in overall survival within 8 yearsd.

The trial randomized 505 high-risk patients in 25 French centers to receive a radiation dose of either 70 Gy or 80 Gy. 

• All patients received 3 years of ADT. (If started today, it may have been 2 years of ADT (see this link) with external beam radiation.) 
• All patients had no detectable cancer in pelvic lymph nodes (N0), but 83% received whole pelvic radiation.
• High-dose patients received IMRT, but many (41%) lower dose patients received 3D-CRT (which is seldom used anymore).

After 10 years of follow-up, only 92 men progressed, which was less than expected. The results were:

• 84% were progression-free in the 80 Gy arm, 72% in the 70 Gy arm. 
• 44% reduction in the biochemical failure rate
• 52% reduction in prostate cancer-specific mortality
• 39% reduction in overal mortality rate
• No difference in late-term urinary or rectal toxicity. Serious (grade 3) toxicity was rare (2-3%)
• No difference in patient-reported quality of life

It comes as no surprise that higher dose radiation to the prostate is more curative. Since there is no toxicity cost to giving the higher dose, it is the clear standard of care.

Several randomized clinical trials (ASCENDE-RT and TROG RADAR) have now proven that increasing the prostate dose with brachytherapy improves outcomes. Clinical trials using SBRT for high-risk patients are underway, and moderate hypofractionation is already standard of care. The FLAME trial showed results can be improved by targeting MRI-detected intraprostatic lesions with a radiation boost. POP-RT showed the importance of whole-pelvic treatment. The whole-pelvic treatment area was expanded (see this link).

STAMPEDE showed that 3 years of abiraterone+ 2 years of ADT improved results over ADT alone. Hormone treatment has been intensified and shortened in the AASUR trial. The PREDICT-RT trial investigates Decipher genomic scores to determine intensity and duration of hormone treatment with apalutamide. DASL-HiCAP tests darolutamide. 

The FDA approval of PSMA PET/CT for high-risk patients improves patient selection. Those found to have distant metastases might be better treated with hormone therapy alone. Those found to have only pelvic lymph node metastases might still be curatively treated with radiation and hormone therapy.