Clinicians and researchers gathered earlier this month at the European Society of Medical Oncology Congress 2024 in Barcelona. Hundreds of presentations covered advances in cancer research, including groundbreaking new clinical trial data in prostate cancer.
While survival for patients with metastatic hormone-sensitive prostate cancer (mHSPC) and with metastatic castration-resistant prostate cancer (mCRPC) has improved in recent years, more treatment options are urgently needed. Below are summaries of four prostate cancer clinical trials that may ultimately lead to improved outcomes for patients: longer, better lives.
The trials are:
- UpFrontPSMA – 177Lu-PSMA-617 followed by with treatment with docetaxel in patients newly diagnosed with metastatic prostate cancer
- ARANOTE – Darolutamide + standard hormone therapy (ADT) vs ADT alone in patients with mHSPC
- PEACE 3 – Combination of radium-223 + enzalutamide compared to enzalutamide alone in patients with mCRPC and bone metastases
- SPLASH – 177Lu-PNT2002 in patients with mCRPC who experience disease progression following treatment with an androgen receptor pathway inhibitor
What this could mean for patients
These new treatments and combinations appear promising in advanced prostate cancer. However, they are not FDA-approved at this time. If you have metastatic prostate cancer, many treatment options are currently available, including ongoing clinical trials. Watch these webinars to learn more, and talk to your doctor.
- PCF webinar on mHSPC
- PCF webinar on mCRPC
- Register for the PCF Virtual Summit on Advanced Prostate Cancer on October 5
177Lu-PSMA-617 followed by docetaxel slows newly-diagnosed metastatic prostate cancer vs. docetaxel alone
177Lu-PSMA-617 is a “radioligand” therapy injected into the bloodstream. It delivers radiation to prostate cancer cells by targeting a molecule called PSMA on their surface, killing the cancer cell. It is currently U.S. FDA-approved for patients with mCRPC that has progressed on other therapies. Additional studies are needed to understand how this treatment could work in earlier stages of prostate cancer. Docetaxel is a chemotherapy drug that is part of the current standard of care for metastatic prostate cancer.
UpFrontPSMA is a Phase 2 clinical trial conducted in Australia testing the efficacy of 177Lu-PSMA-617 “upfront” – that is, in patients newly diagnosed with metastatic prostate cancer – followed by with treatment with docetaxel. Eligible patients had a high volume of disease and high tumor uptake on a PSMA PET scan and PSA greater than 10 at diagnosis. Participants were randomized to treatment with 1) 177Lu-PSMA-617 followed by docetaxel OR 2) docetaxel only. All patients received androgen deprivation therapy (ADT) during the trial. Docetaxel + ADT is current standard of care (i.e., best-practice, accepted treatment) for patients with high-volume metastatic prostate cancer.
Arun A. Azad, MBBS, PhD, of the Peter MacCallum Cancer Centre in Australia, presented the results. 130 participants enrolled in the trial. By many of the key outcomes, participants in the combination therapy group fared better.
- More patients in the 177Lu-PSMA-617 + docetaxel arm had an undetectable PSA 48 weeks after starting treatment compared to the docetaxel control arm (41% vs. 16%).
- An undetectable PSA at any point was observed in 51% and 32% of patients, respectively.
- Patients treated with 177Lu-PSMA-617 were about 40% less likely to have their disease worsen, as shown on scans.
Quality of life and pain scores were similar between groups and stable throughout the study period. Side effects were similar in both arms, with serious events in 27–29% of cases. There were no new safety concerns. As expected, patients in the 177Lu-PSMA-617 arm had a higher frequency of dry mouth (37% versus 0% – all mild to moderate).
Dr. Azad concluded that 177Lu-PSMA-617 potentially has a role in managing mHSPC, though more information is needed. Other study measures (such as time to disease progression on scans) are preliminary.
Adapted from UroToday.com.
Darolutamide + ADT shows benefit vs. ADT alone in metastatic hormone-sensitive prostate cancer
Several medicines are currently used to treat mHSPC. Having an additional option with a different profile of side effects may be better tolerated in some patients. Darolutamide is a type of novel hormone therapy, taken by mouth, that works by blocking activation of the androgen receptor. It is currently FDA-approved for patients with non-metastatic castration-resistant prostate cancer (nmCRPC) and for mHSPC in combination with docetaxel.
ARANOTE is a phase 3 trial comparing darolutamide + standard hormone therapy (ADT) vs ADT alone in patients with mHSPC (as shown on imaging). Fred Saad, MD, of the University of Montreal, presented the results. 669 patients were randomized. He further noted in an interview on UroToday that the study was unique, in that included a diverse racial population: 30% of patients were Asian and about 10% identified as Black.
Darolutamide + ADT slowed the disease more effectively than ADT alone. After 24 months, 30% of participants receiving darolutamide + ADT had worsening of their disease on scans or died, compared with 48% of participants receiving ADT alone. The darolutamide group fared better by other measures, such as being less likely to develop castration resistance, to need additional therapy, and to have worsening pain. Dr. Saad noted that this longer time to developing resistance to treatment is important; it means that the lethal form of the disease is delayed.
Darolutamide was also well-tolerated: side effects were low and similar between groups. Stopping treatment due to treatment-emergent side effects was lower in patients receiving darolutamide versus placebo (6.1% vs 9.0%). Fatigue, a common complaint among patients taking medicines like darolutamide, was actually less frequent in the darolutamide group vs. the placebo group (5.6% vs. 8.1%). Dr. Saad concluded that based on these results for ARANOTE, darolutamide + ADT without docetaxel should become an additional standard of care treatment option for mHSPC.
Adapted from UroToday.com.
Combination of radium-223 + enzalutamide lengthens time to progression vs. enzalutamide alone in mCRPC
Today, there are no curative therapies for metastatic prostate cancer that no longer responds to hormone therapy (mCRPC). To improve on this, one approach is to give two treatments that work in different ways to kill cancer cells. This strategy has the potential to slow progression of the disease and extend life, without increasing side effects.
Radium-223 is radioactive molecule that goes to bones, killing prostate cancer that has metastasized to the bone. Enzalutamide is a type of novel hormone therapy that works by blocking activation of the androgen receptor. Currently, each treatment is approved separately for mCRPC.
PEACE 3 is a Phase 3 trial testing the combination of radium-223 + enzalutamide compared to enzalutamide alone in patients with mCRPC and bone metastases who have minimal or no symptoms (such as bone pain). After the first 119 patients were enrolled, participants were required to receive a bone protecting agent (such as denosumab or a bisphosphonate), in addition to the study treatment.
Silke Gillessen Sommer, MD, of the Oncology Institute of Southern Switzerland, presented the results. 446 patients were enrolled. Patients receiving the combination of enzalutamide + radium-223 had better outcomes vs. enzalutamide alone by several measures, including:
- 31% less likely to have worsening disease on scans or death. The average time to worsening disease was 3 months longer with combination treatment (19.4 months vs. 16.4 months)
- Longer survival: an average of 42.3 months vs. 35 months with enzalutamide alone.
- Fewer patients in the combination arm required additional therapy (30% vs. 51%)
In terms of safety, serious side effects were seen in 28% of patients in the combination group vs. 19% in the enzalutamide group. The most common serious side effects in the combination arm were hypertension (34%), fatigue (5.5%), and fractures (5.1%). Adding a bone protection agent to the treatment protocol reduced rates of fracture in both groups.
Dr. Gillessen Sommer concluded that these results support the combination of enzalutamide + radium-223 (+ a bone protecting agent) as a potential new mCRPC treatment option for patients with prostate cancer and bone metastases who have not received a prior androgen-receptor pathway inhibitor (such as enzalutamide or abiraterone). Study investigator Dr. Karim Fizazi noted that ESMO guidelines will likely be amended soon to reflect this combination as a potential new standard of care.
Adapted from UroToday.com
Promising Results of a Clinical Trial of New PSMA-Targeting Radioligand Therapy
177Lu-PNT2002 is a novel type of “radioligand” therapy consisting of a small molecule linked to a radioactive isotope. 177Lu-PNT2002 delivers PSMA-targeted radiation to prostate cancer cells, causing DNA damage and ultimately cancer cell death. The SPLASH trial is a phase 3 randomized study designed to evaluate the efficacy and safety of 177Lu-PNT2002 in patients with mCRPC who experience disease progression following treatment with an androgen receptor pathway inhibitor (ARPI) such as enzalutamide or abiraterone. To be considered for the trial, patients had to have metastases seen on a PSMA PET scan.
Oliver Sartor, MD, of the Mayo Clinic, presented the results. 412 patients were randomized to treatment with either 177Lu-PNT2002 or the “alternate” ARPI (i.e., enzalutamide if their disease worsened while on abiraterone, or vice versa). Importantly, all patients had access to the study drug: patients in the alternate ARPI treatment arm whose disease progressed could “cross over” and receive 177Lu-PNT2002. This occurred for 85% of the ARPI group.
After an average of 12 months of follow up, the team analyzed the data. Patients in the177Lu-PNT2002 group were about 30% less likely to have worsening disease on scans or death (average time 9.5 months vs. 6 months in the ARPI group). The overall response rate was 38% of patients of the investigational arm vs. 12% of patients in the control arm. The median duration of response was 9.4 and 7.3 months, respectively. Other outcomes such as quality of life and use of pain medications (opioids) also favored 177Lu-PNT2002. Although treatment-emergent side effects were observed in nearly all patients, the side effect burden was generally less with 177Lu-PNT2002.
We don’t know yet whether 177Lu-PNT2002 prolongs life in patients with progressive mCRPC compared with the alternate ARPI medicine. However, these results appear promising.
Adapted from UroToday.com
Read more from ESMO here.